Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors

ABSTRACT

8,9-Dihydroxydihydropyridopyrazine-1,6-diones and 8,9-dihydroxypyridopyrazine-1,6-diones are inhibitors of HIV integrase and inhibitors of HIV replication. In one embodiment, the pyridopyrazinediones are of Formula (I): (I), wherein R 1 , R 2 , R 3 , R 4  and R 5  are defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are described.

This application claims the benefit of U.S. Provisional Application No.60/409,741, filed Sep. 11, 2002, the disclosure of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to dihydroxypyridopyrazine-1,6-dionesand pharmaceutically acceptable salts thereof, their synthesis, andtheir use as inhibitors of the HIV integrase enzyme. The compounds ofthe present invention and their pharmaceutically acceptable salts areuseful for preventing or treating infection by HIV and for treating,delaying the onset of, or preventing AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV. A commonfeature of retrovirus replication is the insertion by virally-encodedintegrase of proviral DNA into the host cell genome, a required step inHIV replication in human T-lymphoid and monocytoid cells. Integration isbelieved to be mediated by integrase in three steps: assembly of astable nucleoprotein complex with viral DNA sequences; cleavage of twonucleotides from the 3′ termini of the linear proviral DNA; covalentjoining of the recessed 3′ OH termini of the proviral DNA at a staggeredcut made at the host target site. The fourth step in the process, repairsynthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acidsequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh et al., EMBOJ. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al.,Nature 1987, 329: 351]. All three enzymes have been shown to beessential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhbitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and of HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. A particular advantage of thepresent invention is highly specific inhibition of HIV integrase and HIVreplication.

The following references are of interest as background:

Chemical Abstracts No. 33-2525 discloses the preparation of5-chloro-8-hydroxy-1,6-naphthyridine-7-carboxylic acid amide from thecorresponding methyl ester.

U.S. Pat. No. 5,294,620 discloses certain 1,6-naphthyridin-2-onederivatives having angiotensin II antagonist activity.

US 2003/0055071 (Publication of U.S. application Ser. No. 09/973,853,filed Oct. 10, 2001) and WO 02/30930 (Publication of InternationalApplication No. PCT/US 01/31456, filed Oct. 9, 2001) each disclosecertain 8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integraseinhibitors, wherein the carboxamido nitrogen is directly or indirectlyattached to phenyl or phenyl fused to a carbocycle. The carboxamides aredisclosed to be useful, inter alia, for treating HIV infection and AIDS.WO 02/30426 discloses another group of8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors,wherein the carboxamido nitrogen is directly or indirectly attached to aheterocycle. WO 02/055079 discloses still another group of8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors,wherein the carboxamido nitrogen is part of a heterocyclic ring system.

WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones tobe HIV integrase inhbitors. The ketones include certain1-aryl-1-(poly)azanaphthylenyl methanones and1-heterocyclyl-1-(poly)azanaphthylenyl methanones. Quinolinyl,naphthyridinyl, and quinoxalinyl are disclosed as suitable(poly)azanaphthalenyl groups in the ketones.

WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides asHIV integrase inhibitors, and WO 03/35077 discloses certainN-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides asHIV integrase inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to noveldihydroxypyridopyrazine-1,6-diones. These compounds and theirpharmaceutically acceptable salts are useful in the inhibition of HIVintegrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS, either as compounds or their pharmaceutically acceptablesalts, or as pharmaceutical composition ingredients, whether or not incombination with other HIV/AIDS antivirals, anti-infectives,immunomodulators, antibiotics or vaccines. More particularly, thepresent invention includes a compound of Formula (I), or apharmaceutically acceptable salt thereof:

wherein

-   -   R¹ is C₁₋₆ alkyl which is substituted with 1 or 2 substituents        each of which is independently:        -   (1) C₃₋₈ cycloalkyl,        -   (2) aryl,        -   (3) a 5- or 6-membered saturated or mono-unsaturated            heterocyclic ring containing from 1 to 4 heteroatoms            independently selected from N, O and S,        -   (4) a 5- or 6-membered heteroaromatic ring containing from 1            to 4 heteroatoms independently selected from N, O and S, or        -   (5) a 9- or 10-membered fused bicyclic heterocycle            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein at least one of the rings is            aromatic;        -   wherein        -   (A) each cycloalkyl is optionally substituted with from 1 to            3 substituents, each of which is independently halo, —C₁₋₆            alkyl, or —O—C₁₋₆ alkyl;        -   (B) each aryl is optionally substituted with from 1 to 5            substituents each of which is independently            -   (1) —C₁₋₆ alkyl, optionally substituted with from 1 to 3                substituents each of which is independently —OH, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),                —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c),                —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),                —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or                —N(R^(a))C(═O)N(R^(a)R^(b)),            -   (2) —O—C₁₋₆ alkyl, optionally substituted with from 1 to                3 substituents each of which is independently —OH,                —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c),                —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)),                —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),                —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),                —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),            -   (3) —C₁₋₆ haloalkyl,            -   (4) —O—C₁₋₆ haloalkyl,            -   (5) —OH,            -   (6) halo,            -   (7) —CN,            -   (8) —NO₂,            -   (9) —N(R^(a)R^(b)),            -   (10) —C(═O)N(R^(a)R^(b)),            -   (11) —C(═O)R^(a),            -   (12) —CO₂R^(c),            -   (13) —SR^(c),            -   (14) —S(═O)R^(c),            -   (15) —SO₂R^(c),            -   (16) —N(R^(a))SO₂R^(c),            -   (17) —SO₂N(R^(a)R^(b)),            -   (18) —N(R^(a))C(═O)R^(b),            -   (19) —N(R^(a))CO₂R^(c), or            -   (20) phenyl;        -   (C) each saturated or mono-unsaturated heterocyclic ring is            -   (i) optionally substituted with from 1 to 5 substituents                each of which is independently halogen, —C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                oxo; and            -   (ii) optionally substituted with 1 or 2 substituents                each of which is independently aryl or a 5- or                6-membered heteroaromatic ring containing from 1 to 4                heteroatoms independently selected from N, O and S; and        -   (D) each heteroaromatic ring or each fused bicyclic            heterocycle is            -   (i) optionally substituted with from 1 to 7 substituents                each of which is independently halogen, —C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                oxo; and            -   (ii) optionally substituted with 1 or 2 substituents                each of which is independently aryl or —C₁₋₆ alkyl-aryl;    -   R² is —H or —C₁₋₆ alkyl;    -   R³ is —H, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, or —C₁₋₆ alkyl        substituted with one of —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,        —CN, —NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),        —CO₂R^(c), —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)),        —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),        —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or        —N(R^(a))C(═O)N(R^(a)R^(b));    -   R⁴ is:        -   (1) —H,        -   (2) —C₁₋₆ alkyl optionally substituted with one of —OH,            —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),            —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O, —N(R^(a))SO₂R^(c),            —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            —N(R^(a))C(═O)N(R^(a)R^(b)), —O—C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)), —S—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),            —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), or            —N(SO₂R^(c))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),        -   (3) —₁₋₆ haloalkyl,        -   (4) —C(═O)R^(a),        -   (5) —CO₂R^(c),        -   (6) —C(═O)N(R^(a)R^(b)),        -   (7) —SO₂N(R^(a)R^(b)),        -   (8) —C₂₋₆ alkenyl,        -   (9) —C₂₋₆ alkenyl-C(═O)—N(R^(a))₂,        -   (10) —C₂₋₅ alkynyl,        -   (11) —C₂₋₅ alkynyl-CH₂N(R^(a))₂,        -   (12) —C₂₋₅ alkynyl-CH₂OR^(a),        -   (13) —C₂₋₅ alkynyl-CH₂S(O)_(n)R^(c), or        -   (14) —R^(k),        -   (15) —C₁₋₆ alkyl substituted with R^(k),        -   (16) —C₁₋₆ haloalkyl substituted with R^(k),        -   (17) —C₁₋₆ alkyl-O—R^(k),        -   (18) —C₁₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),        -   (19) —C₁₋₆ alkyl-S(O)_(n)—R^(k),        -   (20) —C₁₋₆ alkyl-S(O)_(n)C₁₋₆ alkyl-R^(k),        -   (21) —C₁₋₆ alkyl-N(R^(a))—R^(k),        -   (22) —C₁₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-R^(k),        -   (23) —C₁₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-OR^(k), with the            proviso that the —N(R^(a))—moiety and the —OR^(k) moiety are            not both attached to the same carbon of the —C₁₋₆            alkyl-moiety,        -   (24) —C₁₋₆ alkyl-C(═O)—R^(k),        -   (25) —C₁₋₆ alkyl-C(═O)N(R^(a))—R^(k),        -   (26) —C₁₋₆ alkyl-N(R^(a))C(═O)—R^(k),        -   (27) —C₁₋₆ alkyl-C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k), or        -   (28) —C₁₋₆ alkyl-N(R^(a))—C₀₋₆ alkyl-S(O)_(n)R^(k);            -   wherein R^(k) is            -   (i) aryl, which is optionally substituted with from 1 to                5 substituents each of which is independently —C₁₋₆                alkyl, —C₁₋₆ alkyl-OH, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆                alkyl-O—C₁₋₆ haloalkyl, —C₁₋₆ alkyl-N(R^(a)R^(b)), —C₁₋₆                alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(═O)R^(a), —C₁₋₆                alkyl—CO₂R^(c), —₁₋₆ alkyl-S(O)_(n)R^(c), —O—C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halo,                —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),                —CO₂R^(c), —S(O)_(n)R^(c), or —SO₂N(R^(a)R^(b));            -   (ii) a 4- to 7-membered saturated or mono-unsaturated                heterocyclic ring containing at least one carbon atom                and from 1 to 4 heteroatoms independently selected from                N, O and S, wherein the heterocyclic ring is:                -   (a) optionally substituted with from 1 to 5                    substituents each of which is independently halogen,                    —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆                    haloalkyl, or oxo; and                -   (b) optionally mono-substituted with aryl or HetA;                -    wherein HetA is a 5- or 6-membered heteroaromatic                    ring containing from 1 to 4 heteroatoms                    independently selected from N, O and S, wherein the                    heteroaromatic ring is optionally fused with a                    benzene ring, and HetA is optionally substituted                    with from 1 to 4 substituents each of which is                    independently —C₁₋₆ alkyl, —₁₋₆ haloalkyl, —O—C₁₋₆                    alkyl, —O—C₁₋₆ haloalkyl, or oxo; or            -   (iii) a 5- or 6-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S, wherein the heteroaromatic ring is optionally                substituted with from optionally substituted with from 1                to 4 substituents each of which is independently —C₁₋₆                alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆                haloalkyl, or oxo;    -   or alternatively R³ and R⁴ are joined together to form C₅₋₈        cycloalkyl or a 5- to 7-membered saturated heterocyclic ring        containing from 1 to 4 heteroatoms independently selected from        N, O and S; wherein        -   the cycloalkyl is optionally substituted with from 1 to 3            substituents each of which is independently halo, —C₁₋₆            alkyl, or —O—C₁₋₆ alkyl; and        -   the heterocyclic ring is optionally substituted with from 1            to 4 substituents each of which is independently —C₁₋₆            alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or            oxo;    -   or alternatively:        -   (i) R² and R³ together form a direct bond to give a ring            double bond, and R⁴ is an independent group as defined            above;        -   (ii) R² and R³ together with the ring carbon atoms to which            they are attached form a fused cyclopropyl ring which is            optionally substituted at the non-fused cyclopropyl ring            carbon with —OR^(d), and R⁴ is —H; or        -   (iii) R² and R³ together with the ring carbon atoms to which            they are attached form a fused phenyl ring or a fused            pyridyl ring, and R⁴ is absent;    -   R⁵ is:        -   (1) —H,        -   (2) —C₁₋₆ alkyl,        -   (3) —C₁₋₆ alkyl-N(R^(a)R^(b)),        -   (4) —C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),        -   (5) —C₁₋₆ alkyl-C(═O)R^(a),        -   (6) —C₁₋₆ alkyl—CO₂R^(c),        -   (7) —C₁₋₆ alkyl-SR^(c),        -   (8) —C₁₋₆ alkyl—S(═O)R^(c),        -   (9) —C₁₋₆ alkyl-SO₂R^(c),        -   (10) —₁₋₆ alkyl-SO₂N(R^(a)R^(b))        -   (11) —C₁₋₆ haloalkyl,        -   (12) —O—C₁₋₆ alkyl,        -   (13) —O—C₁₋₆ haloalkyl,        -   (14) halo,        -   (15) —CN,        -   (16) —C(═O)R^(a),        -   (17) —CO₂R^(c),        -   (18) —SR^(c),        -   (19) —S(═O)R^(c),        -   (20) —SO₂R^(c),        -   (21) —N(R^(a)R^(b)),        -   (22) —C(═O)N(R^(a)R^(b)), or        -   (23) —SO₂N(R^(a)R^(b));        -   (24) aryl        -   (25) —C₁₋₆ alkyl-aryl        -   (26) HetB,        -   (27) —C₁₋₆ alkyl-HetB,        -   (28) HetC, or        -   (29) —C₁₋₆ alkyl-HetC,        -   wherein            -   HetB is a 5- or 6-membered saturated or mono-unsaturated                ring containing from 1 to 4 heteroatoms independently                selected from N, O and S, wherein the ring is optionally                substituted with from 1 to 5 substituents each of which                is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl,                —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, —C(═O)—C₁₋₆                alkyl, —C(═O)—C₁₋₆ haloalkyl, or —C₁₋₆ alkyl-C₃₋₈                cycloalkyl; and            -   HetC is a 5- or 6-membered heteroaromatic ring                containing from 1 to 4 heteroatoms independently                selected from N, O and S, wherein the heteroaromatic                ring is optionally substituted with from 1 to 4                substituents each of which is independently —C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                oxo;    -   each R^(a) and R^(b) is independently —H or —C₁₋₆ alkyl;    -   each R^(c) is independently a —C₁₋₆ alkyl;    -   R^(d) is a —C₁₋₆ alkyl, allyl, or benzyl; and    -   each n is independently an integer equal to 0, 1 or 2.

An aspect of the present invention is a compound of Formula (I) asdefined above, except that: in the definition of R¹, the optionalsubstitution on each aryl is restricted to 1 to 5 substituents each ofwhich is independently one of groups (1) to (19) (i.e., the choice ofoptional substituents on aryl does not include phenyl); in thealternative definitions of R² and R³, R² and R³ are restricted todefinition (i) (i.e., the formation of a ring double bond; the joiningof R² and R³ to form a fused cyclopropyl ring, a fused phenyl ring, or afused pyridyl ring is excluded); and in the definition of HetB in R⁵,the optional substitution on the saturated or mono-unsaturated ring isrestricted to 1 to 5 substituents each of which is independentlyhalogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,or oxo.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the dihydroxypyridopyrazine-1,6-diones ofFormula (I) above. These compounds and pharmaceutically acceptable saltsthereof are HIV integrase inhibitors.

A first embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is -C₁₋₄alkyl mono-substituted with aryl; wherein the aryl is optionallysubstituted with from 1 to 4 substituents each of which is independently

-   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a)) CO₂R^(c),        —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),        —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (2) —O—C₁₋₄ alkyl, optionally mono-substituted with —OH,            —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —S(O)_(n)R^(c),            —N(R^(a))—CO₂R^(c), —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)),            —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),            —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or            —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (3) —C₁₋₄ haloalkyl,        -   (4) —O—C₁₋₄ haloalkyl,        -   (5) —OH,        -   (6) halo,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —SR^(c),        -   (11) —S(═O)R^(c),        -   (12) —SO₂R^(c),        -   (13) —N(R^(a))SO₂R^(c),        -   (14) —SO₂N(R^(a)R^(b)),        -   (15) —N(R^(a))C(═O)R^(b),        -   (16) —N(R^(a))CO₂R^(c), or        -   (17) phenyl;    -   and all other variables are as originally defined above.

In an aspect of the first embodiment, each of the optional substituentson the aryl is independently one of the groups (1) to (16) set forthabove (i.e., phenyl is excluded as a possible optional substituent).

A second embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is—(CH₂)₁₋₄-phenyl, wherein the phenyl is optionally substituted with from1 to 3 substituents each of which is independently

-   -   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH,            —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),            or —SO₂N(R^(a)R^(b)),        -   (2) —O—C₁₋₄ alkyl,        -   (3) —C₁₋₄ haloalkyl,        -   (4) —O—C₁₋₄ haloalkyl,        -   (5) —OH,        -   (6) halo,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —SR^(c),        -   (11) —S(═O)R^(c),        -   (12) —SO₂R^(c),        -   (13) —N(R^(a))SO₂R^(c),        -   (14) —SO₂N(R^(a)R^(b)),        -   (15) —N(R^(a))C(═O)R^(b),        -   (16) —N(R^(a))CO₂R^(c), or        -   (17) phenyl;

    -   and all other variables are as originally defined above.

In an aspect of the second embodiment, each of the optional substituentson the phenyl is independently one of the groups (1) to (16) set forthabove (i.e., phenyl is excluded as a possible optional substituent).

A third embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is

wherein X¹ and X² are each independently

-   -   (1) —H,    -   (2) methyl,    -   (3) ethyl,    -   (4) methoxy,    -   (5) ethoxy,    -   (6) —CF₃,    -   (7) fluoro,    -   (8) bromo, or    -   (9) chloro,    -   (10) —CN,    -   (11) —S—CH₃, or    -   (12) phenyl;        and all other variables are as originally defined above.

In an aspect of the third embodiment, X¹ and X² are each independentlyselected from one of groups (1) to (9) set forth above (i.e., —CN,—S—CH₃, and phenyl are each excluded as possible substituents).

In another aspect of the third embodiment, R¹ is 4-fluorobenzyl.

A fourth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R² is is —Hor —C₁₋₄ alkyl; and all other variables are as originally defined or asdefined in any of the preceding embodiments or aspects. In an aspect ofthis embodiment, R² is —H.

A fifth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R³ is —H or—C₁₋₄ alkyl; and all other variables are as originally defined or asdefined in any of the preceding embodiments or aspects thereof. In anaspect of this embodiment, R³ is —H.

A sixth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁴ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O, —N(R^(a))SO₂R^(b), or        —N(R^(a))SO₂N(R^(a)R^(b)),    -   (3) —C(═O)N(R^(a)R^(b)),    -   (4) —R^(k),    -   (5) —C₁₋₄ alkyl substituted with R^(k),    -   (6) —C₁₋₄ alkyl-O—R^(k), or    -   (7) —C₁₋₄ alkyl-O—C₁₋₄ alkyl-R^(k);        and all other variables are as originally defined or as defined        in any of the preceding embodiments or aspects thereof.

A seventh embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁴ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH,        —N(R^(a)R^(b)), or —C(═O)N(R^(a)R^(b)),    -   (3) —C(═O)N(R^(a)R^(b)),    -   (4) —(CH₂)₁₋₃—R^(k),    -   (5) —(CH₂)₁₋₃—O—R^(k), or    -   (6) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k);        and all other variables are as originally defined or as defined        in any of the first five embodiments or aspects thereof.

An eighth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R^(k) is:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        alkyl-OH, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄        haloalkyl, —C₁₋₄ alkyl-N(R^(a)R^(b)), —C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₄ alkyl-C(═O)R^(a), —C₁₋₄        alkyl-CO₂R^(c), —C₁₋₄ alkyl—S(O)_(n)R^(c), —O—C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ haloalkyl, —OH, halo, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b));    -   (ii) a 4- to 7-membered saturated heterocyclic ring containing        at least one carbon atom and a total of from 1 to 4 heteroatoms        independently selected from 1 to 4 N atoms, from 0 to 2 O atoms,        and from 0 to 2 S atoms, wherein the heterocyclic ring is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; and        -   (b) optionally mono-substituted with phenyl or HetA;            -   wherein HetA is a 5- or 6-membered heteroaromatic ring                containing a total of from 1 to 4 heteroatoms                independently selected from 1 to 4 N atoms, from 0 to 2                O atoms, and from 0 to 2 S atoms, wherein HetA is                optionally substituted with from 1 to 3 substituents                each of which is independently —C₁₋₄ alkyl, —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; or    -   (iii) a 5- or 6-membered heteroaromatic ring containing a total        of from 1 to 4 heteroatoms independently selected from 1 to 4 N        atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the        heteroaromatic ring is optionally substituted with from        optionally substituted with from 1 to 3 substituents each of        which is independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, —O—C₁₋₆ haloalkyl, or oxo;        and all other variables are as originally defined or as defined        in any of the preceding embodiments or aspects thereof.

In an aspect of the eighth embodiment, HetA is a 5- or 6-memberedheteroaromatic ring containing 1 or 2 N atoms, wherein HetA isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or oxo. In another aspect of the eighth embodiment, HetA ispyrrolyl, pyrazolyl, imidazolyl, pyridyl, or pyrazinyl; which isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl (e.g., methyl), —C₁₋₄ haloalkyl (e.g.,trifluoromethyl), —O—C₁₋₄ alkyl (e.g., methoxy), —O—C₁₋₄ haloalkyl(e.g., —OCF₃), or oxo.

A ninth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R^(k) is:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        alkyl-OH, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄        haloalkyl, —C₁₋₄ alkyl-N(R^(a)R^(b)), —C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₄ alkyl-C(═O)R^(a), —C₁₋₄        alkyl-CO₂R^(c), —C₁₋₄ alkyl—S(O)_(n)R^(c), —O—C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ haloalkyl, —OH, halo, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b)); or    -   (ii) a saturated heterocyclic ring selected from the group        consisting of piperidinyl, morpholinyl, thiomorpholinyl,        thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl,        pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl,        tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl,        thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl,        azepanyl, diazepanyl, thiadiazinanyl, and dioxanyl; wherein the        saturated heterocyclic ring is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; and        -   (b) optionally mono-substituted with phenyl or HetA;

wherein HetA is a heteroaromatic ring selected from the group consistingof pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl,isothiazolyl, and thiadiazolyl; wherein the heteroaromatic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or oxo;

and all other variables are as originally defined or as defined in anyof the first seven embodiments or aspects thereof.

A tenth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ alkyl-N(R^(a)R^(b)),    -   (4) —C₁₋₄ alkyl-C(═O)N(R^(a)R^(b)),    -   (5) —C₁₋₄ alkyl-SO₂N(R^(a)R^(b))    -   (6) —C₁₋₄ haloalkyl,    -   (7) halo,    -   (8) —CN,    -   (9) aryl    -   (10) —C₁₋₄ alkyl-aryl    -   (11) HetB,    -   (12) —C₁₋₄ alkyl-HetB,    -   (13) HetC, or    -   (14) —C₁₋₄ alkyl-HetC,    -   wherein        -   HetB is a 5- or 6-membered saturated ring containing a total            of from 1 to 4 heteroatoms independently selected from 1 to            4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms,            wherein the saturated ring is optionally substituted with            from 1 to 4 substituents each of which is independently            halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,            —O—C₁₋₄ haloalkyl, oxo, —C(═O)—C₁₋₄ alkyl, —C(═O)—C₁₋₄            haloalkyl, or —C₁₋₄ alkyl-C₃₋₆ cycloalkyl; and        -   HetC is a 5- or 6-membered heteroaromatic ring containing a            total of from 1 to 4 heteroatoms independently selected from            1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S            atoms, wherein the heteroaromatic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,            —O—C₁₋₄ haloalkyl, or oxo;            and all other variables are as originally defined or as            defined in any of the preceding embodiments or aspects            thereof.

In an aspect of the tenth embodiment, in the definition of HetB, theoptional substitution on the saturated ring is restricted to 1 to 4substituents each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo.

An eleventh embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

-   -   (1) —H,    -   (2) —C₁₋₄ allyl,    -   (3) —C₁₋₄ alkyl-N(R^(a)R^(b)),    -   (4) halo,    -   (5) —CN, or    -   (6) —C₁₋₄ alkyl-HetB;    -   wherein        -   HetB is a 5- or 6-membered saturated ring containing 1 or 2            N atoms and carbon atoms, wherein the saturated ring is            optionally substituted with from 1 to 4 substituents each of            which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo,            —C(═O)—C₁₋₄ alkyl, —C(═O)—C₁₋₄ haloalkyl, or —C₁₋₄            alkyl-C₃₋₆ cycloalkyl;            and all other variables are as originally defined or as            defined in any of the first nine embodiments or aspects            thereof.

In an aspect of the eleventh, in the definition of HetB, the optionalsubstitution on the saturated ring is restricted to 1 to 4 substituentseach of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo.

In another aspect of the eleventh embodiment, HetB is pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, which isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen (e.g., fluoro, chloro, or bromo), —C₁₋₄ alkyl(e.g., methyl), —C₁₋₄ haloalkyl (e.g., trifluoromethyl), —O—C₁₋₄ alkyl(e.g., methoxy), —O—C₁₋₄ haloalkyl (e.g., —OCF₃), or oxo.

Other embodiments of the present invention include compounds of Formula(I), wherein each R^(a) and R^(b) is independently —H or —C₁₋₄ alkyl;each R^(c) is independently a —C₁₋₄ alkyl; and all other variables areas originally defined or as defined in any of the foregoing embodimentsor aspects thereof.

Still other embodiments of the present invention include compounds ofFormula (I), wherein each R^(a) and R^(b) is independently —H, methyl,or ethyl; each R^(c) is independently methyl or ethyl; and all othervariables are as originally defined or as defined in any of theforegoing embodiments or aspects thereof.

Still other embodiments of the present invention include compounds ofFormula (I), wherein R^(d) is a —C₁₋₄ alkyl (e.g., methyl, ethyl orn-propyl), allyl, or benzyl; and all other variables are as originallydefined or as defined in any of the foregoing embodiments or aspectsthereof.

A class of the present invention includes compounds of Formula (II), ora pharmaceutically acceptable salt thereof:

wherein:

-   -   X¹ and X²′ are each independently:        -   (1) —H,        -   (2) C₁₋₄ alkyl,        -   (2) —O—C₁₋₄ alkyl,        -   (3) —C₁₋₄ haloalkyl,        -   (4) —O—C₁₋₄ haloalkyl,        -   (5) halo,        -   (6) —CN,        -   (7) —S—C₁₋₄ alkyl, or        -   (8) phenyl;    -   R²′ is —H or —C₁₋₄ alkyl;    -   R³′ is —H or —C₁₋₄ alkyl;    -   R⁴′ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH,            —N(R^(a)′R^(b)′), or —C(═O)N(R^(a)′R^(b)′),        -   (3) —C(═O)N(R^(a)′R^(b)′),        -   (4) —(CH₂)₁₋₃—R^(k)′,        -   (5) —(CH₂)₁₋₃—O—R^(k)′, or        -   (6) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k)′;        -   wherein R^(k)′ is:        -   (i) phenyl, which is optionally substituted with from 1 to 3            substituents each of which is independently —C₁₋₄ alkyl,            —O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ haloalkyl, or halo;            or        -   (ii) HetD, wherein HetD is a 5- or 6-membered saturated ring            containing 1 or 2 N atoms, 0 or 1 S atoms, and a balance of            carbon atoms, wherein the saturated ring is optionally            substituted with from 1 to 4 substituents each of which is            independently halo, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄            alkyl, —O—C₁₋₄ haloalkyl, or oxo;            or alternatively:    -   (i) R²′ and R³′ together form a direct bond to give a ring        double bond, and R⁴′ is an independent group as defined above;    -   (ii) R²′ and R³′ together with the ring carbon atoms to which        they are attached form a fused cyclopropyl ring which is        optionally substituted at the non-fused cyclopropyl ring carbon        with —OR^(d)′, and R⁴′ is —H; or    -   (iii) R²′ and R³′ together with the ring carbon atoms to which        they are attached form a fused phenyl ring or a fused pyridyl        ring, and R⁴′ is absent;    -   R⁵′ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl,        -   (3) —C₁₋₄ alkyl-N(R^(a)′R^(b)′),        -   (4) halo,        -   (5) —CN, or        -   (6) —(CH₂)₁₋₃-HetB;        -   wherein            -   HetB is a 5- or 6-membered saturated ring containing 1                or 2 N atoms, zero or 1 O atom, zero or 1 S atom, and a                balance of carbon atoms, wherein the saturated ring is                optionally substituted with from 1 to 4 substituents                each of which is independently halogen, —C₁₋₄ alkyl,                —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo,                —C(═O)—C₁₋₄ alkyl, —C(═O)—C₁₋₄ haloalkyl, or —C₁₋₄                alkyl-C₃₋₆ cycloalkyl;    -   R⁶ is —H or methyl;    -   each R^(a)′ and R^(b)′ is independently —H or —C₁₋₄ alkyl; and    -   R^(d)′ is —C₁₋₄ alkyl, allyl, or benzyl.

A sub-class of the present invention includes compounds of Formula (II),or a pharmaceutically acceptable salt thereof, wherein:

-   -   wherein X¹′ and X²′ are each independently:        -   (1) —H,        -   (2) methyl,        -   (2) —OCH₃,        -   (3) —CF₃,        -   (4) —O—CF₃,        -   (5) chloro,        -   (6) fluoro,        -   (7) bromo;        -   (6) —CN,        -   (7) —S—CH₃, or        -   (8) phenyl;    -   R²′ is —H or methyl;    -   R³′ is —H or methyl;    -   R⁴′ is:        -   (1) —H,        -   (2) methyl,        -   (3) —CH₂OH,        -   (3) —C(═O)N(CH₃)₂,        -   (4) —CH₂—R^(k)′, or        -   (5) -—CH₂—O—CH₂—R^(k)′;            -   wherein R^(k)′ is:            -   (i) phenyl, which is optionally substituted with from 1                to 3 substituents each of which is independently —CH₃,                —OCH₃, —CF₃, —OCF₃, chloro, bromo or fluoro; or            -   (ii) HetD, wherein HetD is a 5- or 6-membered saturated                ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a                balance of carbon atoms, wherein the saturated ring is                optionally substituted with from 1 to 4 substituents                each of which is independently chloro, bromo, fluoro,                —CH₃, —CF₃, —OCH₃, —OCF₃, or oxo;                or alternatively:    -   (i) R²′ and R³′ together form a direct bond to give a ring        double bond, and R⁴′ is an independent group as defined above;    -   (ii) R²′ and R³′ together with the ring carbon atoms to which        they are attached form a fused cyclopropyl ring which is        optionally substituted at the non-fused cyclopropyl ring carbon        with —OMe, —OEt, —O-allyl, or —O-benzyl, and R⁴′ is —H; or    -   (iii) R²′ and R³′ together with the ring carbon atoms to which        they are attached form a fused phenyl ring or a fused pyridyl        ring, and R⁴′ is absent;    -   R⁵ is:        -   (1) —H,        -   (2) methyl,        -   (3) —(CH₂)₁₋₂—N(CH₃)₂,        -   (4) fluoro,        -   (5) bromo,        -   (6) iodo,        -   (7) —CN, or        -   (8) —CH₂-HetB;        -   wherein            -   HetB is a 5- or 6-membered saturated ring containing 1                or 2 N atoms, zero or 1 O atom, zero or 1 S atom, and a                balance of carbon atoms, wherein the saturated ring is                optionally substituted with from 1 to 4 substituents                each of which is independently chloro, bromo, fluoro,                —CH₃, —CF₃, —OCH₃, —OCF₃, oxo, —C(═O)—CH₃, —C(═O)—CF₃,                or —CH₂-cyclopropyl; and    -   R⁶ is —H or methyl.

In an aspect of the preceding sub-class, R²′ and R³′ are each —H ormethyl, with the proviso that R²′ and R³′ are not both methyl; oralternatively R²′ and R³′ together form a direct bond to give a ringdouble bond, with the proviso that when R²′ and R³′ together form adirect bond, R⁴′ is —H.

In another aspect of the preceding sub-class, HetB is pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl, which is optionally substituted with from 1 to 4substituents each of which is independently chloro, bromo, fluoro, —CH₃,—CF₃, —OCH₃, —OCF₃, oxo, —C(═O)—CH₃, —C(═O)—CF₃, or —CH₂-cyclopropyl.

Another sub-class of the present invention includes compounds of Formula(IIa), or a pharmaceutically acceptable salt thereof, wherein:

wherein:

-   -   X¹′ and X²′ are each independently:        -   (1) —H,        -   (2) C₁₋₄ alkyl,        -   (2) —O—C₁₋₄ alkyl,        -   (3) —C₁₋₄ haloalkyl,        -   (4) —O—C₁₋₄ haloalkyl, or        -   (5) halo;    -   R²′ is —H or —C₁₋₄ alkyl;    -   R³′ is —H or —C₁₋₄ alkyl;    -   or alternatively R²′ and R³′ together form a direct bond to give        a ring double bond;    -   R⁴′ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH,            —N(R^(a)′R^(b)′), or —C(═O)N(R^(a)′R^(b)′),        -   (3) —C(═O)N(R^(a)′R^(b)′),        -   (4) —(CH₂)₁₋₃—R^(k)′,        -   (5) —(CH₂)₁₋₃—O—R^(k)′, or        -   (6) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k)′;            -   wherein R^(k)′ is:            -   (i) phenyl, which is optionally substituted with from 1                to 3 substituents each of which is independently —C₁₋₄                alkyl, —O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄                haloalkyl, or halo; or            -   (ii) HetD, wherein HetD is a 5- or 6-membered saturated                ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a                balance of carbon atoms, wherein the saturated ring is                optionally substituted with from 1 to 4 substituents                each of which is independently halo, —C₁₋₄ alkyl, —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo;    -   R⁵′ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl,        -   (3) —C₁₋₄ alkyl-N(R^(a)′R^(b)′),        -   (4) halo,        -   (5) —CN, or        -   (6) —(CH₂)₁₋₃-HetB;        -   wherein            -   HetB is a 5- or 6-membered saturated ring containing 1                or 2 N atoms and carbon atoms, wherein the saturated                ring is optionally substituted with from 1 to 4                substituents each of which is independently halogen,                —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄                haloalkyl, or oxo; and    -   each R^(a)′ and R^(b)′ is independently —H or —C₁₋₄ alkyl.

In an aspect of the preceding sub-class, R²′ and R³′ are each —H ormethyl, with the proviso that R²′ and R³′ are not both methyl; oralternatively R²′ and R³′ together form a direct bond to give a ringdouble bond, with the proviso that when R²′ and R³′ together form adirect bond, R⁴′ is —H.

In another aspect of the preceding sub-class, HetB is pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, which isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen (e.g., fluoro, chloro, or bromo), —C₁₋₄ alkyl(e.g., methyl), —C₁₋₄ haloalkyl (e.g., trifluoromethyl), —O—C₁₋₄ alkyl(e.g., methoxy), —O—C₁₋₄ haloalkyl (e.g., —OCH₃), or oxo.

Still another sub-class of the present invention includes compounds ofFormula (IIa), or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹′ and X²′ are each independently:        -   (1) —H,        -   (2) methyl,        -   (2) —OCH₃,        -   (3) —CF₃,        -   (4) —O—CF₃,        -   (5) chloro,        -   (6) fluoro, or        -   (7) bromo;    -   R²′ is —H or methyl;    -   R³ is —H or methyl;    -   or alternatively R²′ and R³′ together form a direct bond to give        a ring double bond;    -   R⁴′ is:        -   (1) —H,        -   (2) methyl,        -   (3) —CH₂OH,        -   (3) —C(═O)N(CH₃)₂,        -   (4) —CH₂—R^(k)′, or        -   (5) —CH₂—O—CH₂—R^(k)′;            -   wherein R^(k)′ is:            -   (i) phenyl, which is optionally substituted with from 1                to 3 substituents each of which is independently —CH₃,                —OCH₃, —CF₃, —OCF₃, chloro, bromo or fluoro; or            -   (ii) HetD, wherein HetD is a 5- or 6-membered saturated                ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a                balance of carbon atoms, wherein the saturated ring is                optionally substituted with from 1 to 4 substituents                each of which is independently chloro, bromo, fluoro,                —CH₃, —CF₃, —OCH₃, —OCF₃, or oxo; and    -   R⁵′ is:        -   (1) —H,        -   (2) methyl,        -   (3) —(CH₂)₁₋₂—N(CH₃)₂,        -   (4) fluoro,        -   (5) bromo,        -   (6) iodo,        -   (7) —CN, or        -   (8) —CH₂-HetB;        -   wherein            -   HetB is a 5- or 6-membered saturated ring containing 1                or 2 N atoms and carbon atoms, wherein the saturated                ring is optionally substituted with from 1 to 4                substituents each of which is independently chloro,                bromo, fluoro, —CH₃, —CF₃, —OCH₃, —OCF₃, or oxo.

In an aspect of the preceding sub-class, R²′ and R³′ are each —H ormethyl, with the proviso that R²′ and R³′ are not both methyl; oralternatively R²′ and R³′ together form a direct bond to give a ringdouble bond, with the proviso that when R²′ and R³′ together form adirect bond, R⁴′ is —H.

In another aspect of the preceding sub-class, HetB is pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, which isoptionally substituted with from 1 to 4 substituents each of which isindependently chloro, bromo, fluoro, —CH₃, —CF₃, —OCH₃, —OCF₃, or oxo.

Another class of the present invention includes compounds of Formula(III), or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X¹′ and X²′ are each independently —H or halo;    -   and all other variables are as set forth in Formula (II) for the        preceding class. A sub-class of this class includes compounds of        Formula (III), or a pharmaceutically acceptable salt thereof,        wherein X¹′ and X²′ are each independently -H or halo; and all        other variables are as defined above in any one of the        sub-classes of the preceding class defined by Formula (II)        (including sub-classes defined by Formula (IIa)). Aspects of        this sub-class are analogous to the aspects set forth above for        the preceding Formula (II) sub-class (including aspects defined        by Formula (IIa)).

Another sub-class of this class includes compounds of Formula (III), ora pharmaceutically acceptable salt thereof, wherein X¹′ and X²′ are eachindependently —H, fluoro, chloro, or bromo; and all other variables areas defined for the class or as defined in a sub-class thereof. In stillanother sub-class, X¹′ is fluoro and X²′ is —H; and all other variablesare as defined for the class or as defined in a sub-class thereof.

Other embodiments of the present invention include compounds of Formula(II), (IIa), or (III) respectively, wherein each R^(a)′ and R^(b)′ isindependently —H or —C₁₋₄ alkyl; and all other variables are asoriginally defined or as defined in any of the foregoing embodiments oraspects thereof.

Still other embodiments of the present invention include compounds ofFormula (II), (IIa), or (III) respectively, wherein each R^(a)′ andR^(b)′ is independently —H, methyl, or ethyl; and all other variablesare as originally defined or as defined in any of the foregoingembodiments or aspects thereof.

Still other embodiments of the present invention include compounds ofFormula (II), wherein R^(d)′ is a —C₁₋₄ alkyl (e.g., methyl, ethyl orn-propyl), allyl, or benzyl; and all other variables are as originallydefined or as defined in any of the foregoing embodiments or aspectsthereof.

Another embodiment of the present invention is a compound selected fromthe group consisting of

-   -   2-benzyl-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-iodo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(3-chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-(3,4-dichlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(3,4-difluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-(3-chloro-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(3-chloro-4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(dimethylamino)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-benzyl-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-(4-fluorobenzyl)-8,9-dihydroxy4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-pyrazine-7-carbonitrile;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   4-[(benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   4(hydroxymethyl)-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   4-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(morpholin-4-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(thiomorpholin-4-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-[4-fluoro-2-(methylthio)benzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   7-[(1-acetylpiperidin-4-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(4-fluorobenzyl)-8,9-dihydroxy-7-{[1-(trifluoroacetyl)piperidin-4-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   7-{[1-(cyclopropylmethyl)piperidin-3-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   7-[(1-acetylpiperidin-3-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   7-[(1-acetylpiperidin-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   7-{[1-(cyclopropylmethyl)piperidin-2-yl]methyl)        -2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   2-(3-cyanobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    -   2-(biphenyl-3-ylmethyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido        [1,2-a]pyrazine-1,6-dione    -   (±)-1-[(benzyloxy)methyl]-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;    -   (±)-1-(methoxymethyl)-2-(4-fluorobenzyl)4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;    -   (±)-1-[(allyloxy)methyl]-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;    -   (±)-1-(ethoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;    -   (±)-1-(n-propoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;    -   2-[1-(4-fluorophenyl)ethyl]-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;    -   5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a]quinoxaline-6,10-dione;    -   5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:3′,2′-e]pyrazine-6,10-dione;    -   5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:2′,3′-e]pyrazine-6,10-dione;    -   and pharmaceutically acceptable salts thereof.

Other embodiments of the present invention include the following:

-   -   (a) A pharmaceutical composition comprising a therapeutically        effective amount of a compound of the invention (e.g., a        compound of Formula (I) or Formula (II) or Formula (III) or any        of the specific compounds set forth above) and a        pharmaceutically acceptable carrier.    -   (b) A pharmaceutical composition which comprises the product        prepared by combining (e.g., mixing) a therapeutically effective        amount of a compound of the invention and a pharmaceutically        acceptable carrier.    -   (c) The pharmaceutical composition of (a) or (b), further        comprising a therapeutically effective amount of an HIV        infection/AIDS treatment agent selected from the group        consisting of HIV/AIDS antiviral agents, immunomodulators, and        anti-infective agents.    -   (d) The pharmaceutical composition of (c), wherein the HIV        infection/AIDS treatment agent is an antiviral selected from the        group consisting of HIV protease inhibitors, non-nucleoside E[V        reverse transcriptase inhibitors, and nucleoside HIV reverse        transcriptase inhibitors.    -   (e) A combination useful for inhibiting HIV integrase, for        treating or preventing infection by HIV, or for preventing,        treating or delaying the onset of AIDS, which is a        therapeutically effective amount of a compound of the invention        and a therapeutically effective amount of an HIV infection/AIDS        treatment agent selected from the group consisting of HIV/AIDS        antiviral agents, immunomodulators, and anti-infective agents.    -   (f) The combination of (e), wherein the HIV infection/AIDS        treatment agent is an antiviral selected from the group        consisting of HIV protease inhibitors, non-nucleoside HIV        reverse transcriptase inhibitors and nucleoside HIV reverse        transcriptase inhibitors.    -   (g) A method of inhibiting HIV integrase in a subject in need        thereof which comprises administering to the subject a        therapeutically effective amount of a compound of the invention.    -   (h) A method of preventing or treating infection by HIV in a        subject in need thereof which comprises administering to the        subject a therapeutically effective amount of a compound of the        invention.    -   (i) The method of (h), wherein the compound of the invention is        administered in combination with a therapeutically effective        amount of at least one antiviral selected from the group        consisting of HIV protease inhibitors, non-nucleoside HIV        reverse transcriptase inhibitors, and nucleoside HIV reverse        transcriptase inhibitors.    -   (j) A method of preventing, treating or delaying the onset of        AIDS in a subject in need thereof which comprises administering        to the subject a therapeutically effective amount of a compound        of the invention.    -   (k) The method of (j), wherein the compound is administered in        combination with a therapeutically effective amount of at least        one antiviral selected from the group consisting of HIV protease        inhibitors, non-nucleoside HIV reverse transcriptase inhibitors,        and nucleoside HIV reverse transcriptase inhibitors    -   (l) A method of inhibiting HIV integrase in a subject in need        thereof which comprises administering to the subject the        pharmaceutical composition of (a), (b), (c) or (d) or the        combination of (e) or (f).    -   (m) A method of preventing or treating infection by HIV in a        subject in need thereof which comprises administering to the        subject the pharmaceutical composition of (a), (b), (c) or (d)        or the combination of (e) or (f).    -   (n) A method of preventing, treating or delaying the onset of        AIDS in a subject in need thereof which comprises administering        to the subject the pharmaceutical composition of (a), (b), (c)        or (d) or the combination of (e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HIV protease, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreHIV/AIDS treatment agents selected from HIV/AIDS antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, or an aspect or feature or sub-feature thereof, describedabove.

In all of the foregoing embodiments describing compositions,combinations and methods, the compound may optionally be used in theform of a pharmaceutically acceptable salt.

As used herein, the term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means a linearor branched chain alkyl group having from 1 to 6 carbon atoms andincludes all of the hexyl alkyl and pentyl alkyl isomers as well as n-,iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl”means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “C₀” as employed in expressions such as “—C₀₋₆ alkyl-” means adirect covalent bond. For example, in the group —C₁₋₆alkyl—N(R^(a))—C₀₋₆ alkyl-S(O)_(n)R^(k), when the second alkylene groupis “C₀”, then the group is —C₁₋₆ alkyl—N(R^(a))—S(O)_(n)R^(k).

The term “—C₁₋₆ alkyl-” refers to a C₁ to C₆ linear or branched alkylgroup as just defined which is bivalent. It can alternatively bereferred to as “C₁₋₆ alkylene” or “C₁₋₆ alkanediyl”. A class ofalkylenes of particular interest with respect to the invention is—(CH₂)₁₋₆—, and sub-classes of particular interest include —(CH₂)₁₋₄—,—(CH₂)₁₋₃—, —(CH₂)₁₋₂—, and —CH₂—.

The term “C₂₋₆ alkenyl” (or “C₂-C₆ alkenyl”) means a linear or branchedchain alkenyl group having from 2 to 6 carbon atoms and includes all ofthe hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl,3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).Similar terms such as “C₂₋₄ alkenyl” have an analogous meaning. A classof alkenyls of particular interest with respect to the invention is—CH₂═CH—(CH₂)₀₋₄. H, and sub-classes of particular interest include—CH═CH—(CH₂)₁₋₂H, —CH═CH—CH₃, and —CH═CH₂. Another class of alkenyls ofparticular interest with respect to the invention is alkenyls selectedfrom —(CH₂)₂—CH═CH—(CH₂)₀₋₂H and —CH₂—CH═CH—(CH₂)₀₋₃H.

The term “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) means a linear or branchedchain alkynyl group having from 2 to 5 carbon atoms and includes all ofthe pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl,1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms suchas “C₂₋₄ alkynyl” have an analogous meaning. A class of alkynyls ofparticular interest with respect to the invention is —C≡C—(CH₂)₁₋₄H(e.g., —C≡C—CH₃). Another class of alkynyls of particular interest withrespect to the invention is alkynyls selected from —CH₂—≡—(CH₂)₁₋₃H and—(CH₂)₂—≡—(CH₂)₁₋₂H.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ringof an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). Similar terms such as “C₃₋₆ cycloalkyl” have an analogousmeaning.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. A class of fluoroalkyls ofparticular interest with respect to the invention is the series(CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “oxo” means a divalent oxygen substituent; i.e., ═O. An oxosubstituent on a carbon atom in a heteroaromatic ring refers to the ketoform of the keto-enol tautomer, as exemplified here for an oxopyridinylsubstituent:

Compounds of the present invention having an oxo substituent on a carbonatom of a heteroaromatic ring are understood to include compounds inwhich only the keto form is present, compounds in which only the enolform is present, and compounds in which the keto and enol forms are bothpresent.

The term “aryl” as used herein refers to an aromatic carbocyclic ring oran aromatic carbocyclic fused ring system. The fused ring systemcontains two or more carbocyclic rings in which each ring shares twoadjacent carbon atoms with at least one other ring. The aryl group maybe attached to the rest of the molecule at any carbon atom which resultsin a stable compound. A subset of aryl groups particularly suitable foruse in the present invention (e.g., in the definition of R^(k)) includesthose selected from phenyl, naphthyl, anthryl, and phenanthryl. Anotherparticularly suitable subset of aryl groups is phenyl and naphthyl.Still another particularly suitable subset of aryl groups is phenyl perse.

The term “heterocyclic ring” refers to a 4- to 8-membered, saturated orunsaturated monocyclic ring that contains one or more heteroatoms (e.g.,from 1 to 6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1heteroatom) independently selected from N, O and S and a balance ofcarbon atoms (the ring typically contains at least one carbon atom); andwherein any one or more of the nitrogen and sulfur heteroatoms isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The heterocyclic ring may be attached to therest of the molecule via any heteroatom or carbon atom in the ring,provided that attachment results in the creation of a stable structure.When the heterocyclic ring has substituents, it is understood that thesubstituents may be attached to any atom in the ring, whether aheteroatom or a carbon atom, provided that a stable chemical structureresults.

A subset of the heterocyclic rings useful in the present invention(e.g., in the definition of R^(k)) includes any 4 to 7-memberedsaturated or mono-unsaturated heterocyclic ring, wherein the ringcontains at least one carbon atom and from 1 to 4 heteroatomsindependently selected from N, O and S. A subgroup of this subsetincludes any 4- to 7-membered saturated or mono-unsaturated heterocyclicring in which the ring contains at least one carbon atom and a total offrom 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from0 to 2 O atoms, and from 0 to 2 S atoms. Representative examples ofsaturated heterocyclic rings include piperidinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl,hexahydropyrimidinyl, thiazinanyl

thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl

diazepanyl, thiadiazinanyl,

and dioxanyl. Representative examples of mono-unsaturated rings are thesame as the saturated rings listed in the preceding sentence except thateach ring contains a double bond.

Another subset of the heterocyclic rings useful in the present invention(e.g., in the definition of HetB) includes any 5- or 6-memberedsaturated or mono-unsaturated ring containing from 1 to 4 heteroatomsindependently selected from N, O and S. A useful subgroup of this subsetincludes any 5- or 6-membered saturated or mono-unsaturated heterocyclicring in which the ring contains at least one carbon atom and a total offrom 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from0 to 2 O atoms, and from 0 to 2 S atoms. Another useful subgroup isidentical to the preceding subgroup, except that it is limited tosaturated heterocyclic rings. Still another subgroup of this subset ofheterocyclic rings suitable for use in the present invention includesany 5- or 6-membered saturated ring containing 1 or 2 N atoms and carbonatoms. Representative examples of this subgroup include piperidinyl,pyrazolidinyl, imidazolidinyl, piperazinyl, piperidinyl, andhexahydropyrimidinyl.

Another subset of the heterocyclic rings useful in the present invention(e.g., in the definition of HetD) includes any 5- or 6-memberedsaturated ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a balanceof carbon atoms.

Still another subset of the heterocyclic rings useful in the presentinvention are the heteroaromatic rings. The term “heteroaromatic ring”(alternatively “heteroaryl ring”) generally refers to a heterocyclicring as defined above in which the ring is an aromatic ring. A usefulsubgroup of this subset (e.g., in the definition of R^(k), HetA, orHetC) includes any 5- or 6-membered monocyclic aromatic ring whichconsist of carbon atoms and from 1 to 4 heteroatoms independentlyselected from N, O and S. Representative examples of this subgroupinclude pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Another usefulsubgroup of this subset includes any 5- or 6-membered heteroaromaticring in which the ring contains a total of from 1 to 4 heteroatomsindependently selected from 1 to 4 N atoms, from 0 to 2 O atoms, andfrom 0 to 2 S atoms. Another useful subgroup includes any 5- or6-membered heteroaromatic ring containing 1 or 2 N atoms and carbonatoms.

The term “fused bicyclic heterocycle” refers to any 8- to 12-memberedbicyclic ring system containing one or more heteroatoms (e.g., from 1 to6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom) independentlyselected from N, O and S, in which one ring contains all of theheteroatoms or each ring contains at least one of the heteroatoms, andwherein each ring is saturated or unsaturated, and two adjacent ringatoms are shared by each of the rings in the ring system and each of thetwo shared atoms is independently a carbon atom or a heteroatom. Any oneor more of the nitrogen and sulfur heteroatoms in the ring system isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The fused bicyclic heterocycle may be attachedto the rest of the molecule via any heteroatom or carbon atom in thering, provided that attachment results in the creation of a stablestructure. When the bicyclic heterocycle has substituents, it isunderstood that the substituents may be attached to any atom in thering, whether a heteroatom or a carbon atom, provided that a stablechemical structure results.

A subset of the fused bicyclic heterocycles useful in the presentinvention (e.g., in the definition of R¹) includes any 9- or 10-memberedfused bicyclic heterocycle containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein at least one of therings is aromatic. Representative examples of bicyclic heterocycles inthis subset include benzotriazolyl, indolyl, isoindolyl, indazolyl,indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo-1,4-dioxinyl

and benzo-1,3-dioxolyl

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocyclic ring described as containing from“1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4heteroatoms.

When any variable (e.g., R^(a), R^(b), or R^(c)) occurs more than onetime in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “each aryl is optionally substitutedwith from 1 to 5 substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

The symbol “

” in front of an open bond in the structural formula of a group marksthe point of attachment of the group to the rest of the molecule.

The compounds of the present invention may have asymmetric centers andmay occur, except when specifically noted, as mixtures of stereoisomersor as individual diastereomers, or enantiomers, with all isomeric formsbeing included in the present invention.

As would be recognized by one of ordinary skill in the art, all of thecompounds of the present invention can exist as tautomers such as thefollowing:

It is to be understood for the purposes of the present invention that areference herein to a compound of Formula I is a reference to compound Iper se, or to any one of its tautomers per se (e.g., IA, IB, IC, ID orIE), or to mixtures of two or more tautomers (e.g., two or more of I,IA, IB, IC, ID and IE).

The compounds of the present invention are useful in the inhibition ofHIV integrase, the prevention or treatment of infection by humanimmunodeficiency virus (HIV) and the prevention, treatment or the delayin the onset of consequent pathological conditions such as AIDS.Preventing AIDS, treating AIDS, delaying the onset of AIDS, orpreventing or treating infection by HIV is defined as including, but notlimited to, treatment of a wide range of states of HIV infection: AIDS,ARC (AIDS related complex), both symptomatic and asymptomatic, andactual or potential exposure to HIV. For example, the compounds of thisinvention are useful in treating infection by HIV after suspected pastexposure to HIV by such means as blood transfusion, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The compounds of the present invention can be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. When the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof caninclude alkali metal salts (e.g., sodium or potassium salts), alkalineearth metal salts (e.g., calcium or magnesium salts), and salts formedwith suitable organic ligands such as quaternary ammonium salts. Also,in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify thesolubility or hydrolysis characteristics of the compound.

For the purpose of preventing or treating HIV infection or preventing,treating or delaying the onset of AIDS, the compounds of the presentinvention can be administered orally, parenterally (includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques), by inhalation spray, or rectally, inthe form of a unit dosage of a pharmaceutical composition containing atherapeutically effective amount of the compound and conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound to the individual in need of treatment. When a compound of theinvention is provided in combination with one or more other activeagents (e.g., antiviral agents useful for treating HIV infection orAIDS), “administration” and its variants are each understood to includeconcurrent and sequential provision of the compound and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombining the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (which may be alternatively referred to herein as“patient”) as used herein refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated. When the active compound (i.e., activeingredient) is administered as the salt, references to the amount ofactive ingredient are to the free acid or free base form of thecompound.

The pharmaceutical compositions can be in the form oforally-administrable suspensions or tablets or capsules, nasal sprays,sterile injectible preparations, for example, as sterile injectibleaqueous or oleagenous suspensions or suppositories. These compositionscan be prepared by methods and contain excipients which are well knownin the art. Suitable methods and ingredients are described inRemington's Pharmaceutical Sciences, 18^(th) edition, edited by A. R.Gennaro, Mack Publishing Co., 1990, which is herein incorporated byreference in its entirety.

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One preferred dosage range is 0.01to 500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreagents useful in the treatment of HIV infection or AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more of the HIV/AIDS antivirals,imunomodulators, antiinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable antiviral agents include those listed in thefollowing TABLE Manufacturer (Tradename and/or Drug Name Location)Indication (Activity) abacavir Glaxo Welcome HIV infection, AIDS, ARC(nRTI) GW 1592 (ZIAGEN ®) 1592U89 abacavir + lamivudine +GlaxoSmithKline HIV infection, AIDS, ARC zidovudine (TRIZIVIR ®) (nRTIs)acemannan Carrington Labs ARC (Irving, TX) ACH 126443 Achillion Pharm.HIV infections, AIDS, ARC (nRTI) acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC, in combination with AZT AD-439 Tanox BiosystemsHIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS,ARC adefovir dipivoxil Gilead HIV infection, AIDS, ARC GS 840 (reversetranscriptase inhibitor) AL-721 Ethigen ARC, PGL, HIV positive, (LosAngeles, CA) AIDS alpha interferon GlaxoSmithKline Kaposi's sarcoma,HIV, in combination w/Retrovir AMD3100 AnorMed HIV infection, AIDS, ARC(CXCR4 antagonist) amprenavir GlaxoSmithKline HIV infection, AIDS, 141W94 (AGENERASE ®) ARC (PI) GW 141 VX478 (Vertex) ansamycin AdriaLaboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) antibodywhich neutralizes Advanced Biotherapy AIDS, ARC pH labile alpha aberrantConcepts (Rockville, interferon MD) AR177 Aronex Pharm HIV infection,AIDS, ARC atazanavir (BMS 232632) Bristol-Myers Squibb HIV infection,AIDS, ARC (REYATAZ ™) (PI) beta-fluoro-ddA Nat'l Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection,AIDS, (CGP-73547) Novartis ARC (PI) BMS-234475 Bristol-Myers Squibb/ HIVinfection, AIDS, (CGP-61755) Novartis ARC (PI) capravirine Pfizer HIVinfection, AIDS, (AG-1549, S-1153) ARC (nnRTI) CI-1012 Warner-LambertHIV-1 infection cidofovir Gilead Science CMV retinitis, herpes,papillomavirus curdlan sulfate AJI Pharma USA HIV infectioncytomegalovirus immune MedImmune CMV retinitis globin cytovene Syntexsight threatening CMV ganciclovir peripheral CMV retinitis delavirdinePharmacia-Upjohn HIV infection, AIDS, (RESCRIPTOR ®) ARC (nnRTI) dextranSulfate Ueno Fine Chem. Ind. AIDS, ARC, HIV Ltd. (Osaka, Japan) positiveasymptomatic ddC Hoffman-La Roche HIV infection, AIDS, ARC (zalcitabine,(HIVID ®) (nuclesodie reverse dideoxycytidine) transcriptase inhibitor)ddI Bristol-Myers Squibb HIV infection, AIDS, ARC; (didanosine,(VIDEX ®) combination with AZT/d4T dideoxyinosine) (nRTI) DPC 681 & DPC684 DuPont HIV infection, AIDS, ARC (PIs) DPC 961 & DPC 083Bristol-Myers Squibb HIV infection AIDS, ARC (from DuPont Pharma)(nnRTIs) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) efavirenzBristol-Myers Squibb HIV infection, AIDS, (DMP 266) (SUSTIVA ®) ARC(non-nucleoside RT Merck (STOCRIN ®) inhibitor) famciclovir Novartisherpes zoster, herpes (FAMVIR ®) simplex emtricitabine Gilead (fromTriangle HIV infection, AIDS, ARC FTC Pharmaceuticals) (nRTI)(COVIRACIL ®) Emory University emvirine Gilead (from Triangle HIVinfection, AIDS, ARC Pharmaceuticals) (nnRTI) (COACTINON ®) enfuvirtideTrimeris & Roche HIV infection, AIDS, ARC T-20 (FUZEON ®) (fusioninhibitor) HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC(nnRTI) fosamprenavir Glaxo Smith Kline HIV infection, AIDS, ARC(prodrug of amprenavir) hypericin VIMRx Pharm. HIV infection, AIDS, ARCrecombinant human Triton Biosciences AIDS, Kaposi's sarcoma, interferonbeta (Almeda, CA) ARC interferon alfa-n3 Interferon Sciences ARC, AIDSindinavir Merck (CRIXIVAN ®) HIV infection, AIDS, ARC, asymptomatic HIVpositive, (PI) ISIS 2922 ISIS Pharmaceuticals CMV retinitisJE2147/AG1776 Agouron HIV infection, AIDS, ARC (PI) KNI-272 Nat'l CancerInstitute HIV-assoc. diseases lamivudine, 3TC GlaxoSmithKline HIVinfection, AIDS, (EPIVIR ®) ARC (nRTI) lamivudine + zidovudineGlaxoSmithKline HIV infection, AIDS, (COMBIVIR ®) ARC (nRTI) lobucavirBristol-Myers Squibb CMV infection lopinavir (ABT-378) Abbott HIVinfection, AIDS, ARC (PI) lopinavir + ritonavir Abbott (KALETRA ®) HIVinfection, AIDS, ARC (ABT-378/r) (PI) mozenavir AVID (Camden, NJ) HIVinfection, AIDS, ARC (DMP-450) (PI) nelfinavir Agouron HIV infection,AIDS, (VIRACEPT ®) ARC (PI) nevirapine Boeheringer HIV infection, AIDS,Ingleheim ARC (nnRTI) (VIRAMUNE ®) novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) peptide T Peninsula Labs AIDS octapeptide(Belmont, CA) sequence PRO 140 Progenics HIV infection, AIDS, ARC (CCR5co-receptor inhibitor) PRO 542 Progenics HIV infection, AIDS, ARC(attachment inhibitor) trisodium Astra Pharm. Products, CMV retinitis,HIV infection, phosphonoformate Inc other CMV infections PNU-140690Pharmacia Upjohn HIV infection, AIDS, ARC (PI) probucol Vyrex HIVinfection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection, AIDS,(Houston TX) ARC ritonavir Abbott (NORVIR ®) HIV infection, AIDS,(ABT-538) ARC (PI) saquinavir Hoffmann-LaRoche HIV infection, AIDS,(FORTOVASE ®) ARC (PI) stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, ARC didehydrodeoxy- (ZERIT ®) (nRTI) thymidine T-1249Trimeris HIV infection, AIDS, ARC (fusion inhibitor) TAK-779 Takeda HIVinfection, AIDS, ARC (injectable CCR5 receptor antagonist) tenofovirGilead (VIREAD ®) HIV infection, AIDS, ARC (nucleotide reversetranscriptase inhibitor) tipranavir (PNU-140690) Boehringer IngelheimHIV infection, AIDS, ARC (PI) TMC-120 & TMC-125 Tibotec HIV infections,AIDS, ARC (nuRTIs) TMC-126 Tibotec HIV infection, AIDS, ARC (PI)valaciclovir GlaxoSmithKline genital HSV & CMV infections virazoleViratek/ICN (Costa asymptomatic HIV positive, ribavirin Mesa, CA) LAS,ARC zidovudine; AZT GlaxoSmithKline HIV infection, AIDS, ARC,(RETROVIR ®) Kaposi's sarcoma in combination with other therapies (nRTI)PI = protease inhibitornnRTI = non-nucleoside reverse transcriptase inhibitornRTI = nucleoside reverse transcriptase inhibitor

A compound of the present invention can also be administered incombination with an HIV integrase inhibitor such as a compound describedin WO 99/62513,WO 99/62520, or WO 99/62897. A compound of the presentinvention can also be administered in combination with a CCR5 receptorantagonist, such as a compound described in WO 99/04794, WO 99/09984, WO99/38514, WO 00/59497, WO 00/59498, WO 00/59502, WO 00/59503, WO00/76511, WO 00/76512, WO 00/76513, WO 00/76514, WO 00/76792, or WO00/76793. The compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure,in combination with effective amounts of one or more HIV/AIDSantivirals, immunomodulators, antiinfectives, or vaccines useful fortreating HIV infection or AIDS disclosed in the Table in WO 02/30930,which is herein incorporated by reference in its entirety.

It will be understood that the scope of combinations of the compounds ofthis invention with HIV/AIDS antivirals, immunomodulators,anti-infectives or vaccines is not limited to those described orreferenced above, but includes in principle any combination with anypharmaceutical composition useful for the treatment of AIDS. TheHIV/AIDS antivirals and other agents will typically be employed in thesecombinations in their conventional dosage ranges and regimens asreported in the art, including the dosages described in the Physicians'Desk Reference, 54^(th) edition, Medical Economics Company, 2000. Thedosage ranges for a compound of the invention in these combinations arethe same as those set forth above.

Abbreviations used in the instant specification, particularly theSchemes and Examples, include the following:

-   -   AIDS=acquired immunodeficiency syndrome    -   ARC=AIDS related complex    -   Bn=benzyl    -   BOP=benzotriazol-1-yloxytris-(dimethylamino)phosphonium        hexafluorophosphate    -   CBZ=carbobenzoxy (alternatively, benzyloxycarbonyl)    -   DMAP=dimethylaminopyridine    -   DMF=dimethylformamide    -   DMSO=dimethyl sulfoxide    -   EDC or EDAC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   ES-MS=eletron spray mass spectroscopy    -   Et=ethyl    -   FT ICR=fourier transform ion cyclotron resonance    -   Hal=halide    -   HIV=human immunodeficiency virus    -   HOBt=1-hydroxy benzotriazole hydrate    -   HPLC=high performance liquid chromatography    -   LC=liquid chromatography    -   Me=methyl    -   MS=mass spectroscopy    -   NBS=N-bromosuccinimide    -   NMR=nuclear magnetic resonance    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

The compounds of the present invention,8,9-dihydroxydihydropyridopyrazine-1,6-diones and8,9-dihydroxypyridopyrazine-1,6-diones, can be prepared by subjecting1-alkyl-4-acyl piperazin-2-ones and1-alkyl-4-acyl-3,4-dihydropyrazine-2(1H)-ones, respectively, to anoxalation-cyclization sequence. Scheme 1 depicts the general approach tothe preparation of compounds of Formula (I). In Scheme 1,piperazin-2-one 1-1 is treated with oxalate 1-2 in the presence of base(e.g., lithium or sodium bis(trimethylsilyl)amide, or lithiumdiisopropylamide) at low temperature (e.g., from about 0 to about 25°C.) in an anhydrous non-protic solvent (e.g., DMF) to give adihydroxypyridopyrazinedione of Formula (I). Scheme 2 exemplifies thesame approach for the preparation of compounds of Formula (II). Ananalogous procedure can be used to prepare compounds of Formula (III) asearlier defined and described.

1-Alkyl-4-acyl piperazin-2-ones of formula 1-1 can be prepared byalkylating a piperazin-2-one having a protective group on the4-piperazinyl nitrogen, deprotecting the alkylated product, and thenacylating with a suitable acylating agent to introduce R⁵. Theprotection and deprotection of the amine in the piperazin-2-one can beaccomplished using conventional amine protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973 and in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Furtherdescription of the preparation of piperazin-2-ones 1-1 via thischemistry is provided in Bernotas et al., Tetrahedron Lett. 1996, 7339;Saari et al., J. Med. Chem. 1990, 2590; Sugihara et al., J. Med. Chem.1998, 489. This method is exemplified in Scheme 3 for the preparation ofcompound 2-1, wherein CBZ-protected piperazin-2-one 3-1 is alkylatedwith benzyl halide (e.g., benyl bromide) 3-2 in the presence of a base(e.g., in the presence of Li or Na bis(trimethylsilyl)amide or Lidiisopropylamide at 0-25° C. in an anhydrous non-protic solvent such asDMF), and the alkylated product 3-3 is then treated with a reducingagent (e.g., H₂ over Pd/C) to remove the CBZ protective group. Thedeprotected product is then acylated with anhydride 3-4 to afford 2-1.Further description of this chemistry can be found in Wei et al.,Bioorg. Med. Chem. 2000, 1737. Compound 3-1 can be prepared usingmethods described in Choi et al., J. Med. Chem. 1999, 3647;Najman-Bronzewska et al., Pharmazie 1997, 198; Fryer et al., J. Org.Chem. 1991, 3715, or routine variations thereof.

Other methods for preparing piperazin-2-ones 1-1 are exemplified inSchemes 4 and 5 showing the preparation of piperazin-2-ones 2-1 and 5-4respectively. (Note: Piperazin-2-one 5-4 is equivalent to 2-1 havingR²′═R³′═R⁴′═H.) In Scheme 4, 4-acylpiperazin-2-one 4-1 is alkylated withbenzyl halide (e.g., benzyl bromide) 3-2 in the presence of a base suchas Li or Na bis(trimethylsilyl)amide or Li diisopropylamide at lowtemperature (e.g., 0 to 25° C.) in an anhydrous non-protic solvent suchas DMF. Further description of this chemistry can be found in Hori etal., Chem. Pharm. Bull. 1981, 1594. In Scheme 5,N-(2,2-dimethoxyethyl)-N-benzylamine is obtained by reductive alkylationof the corresponding benzaldehyde and dimethoxyethylamine. Thealkylation product is acylated with N-acyl-glycine with standardcoupling reagents (eg. EDC, BOP, etc). Treatment of the acylationproduct with acid (e.g., MeSO₃H in CH₂Cl₂, Kim et al., Heterocycles1998, 2279; aqueous TFA, Horwell et al., Tetrahedron 1998, 4591; p-TsOHin toluene, Uchida et al., Chem. Pharm. Bull. 1997, 1228;HCl-acetonitrile, Kurihara et al., Heterocycles 1982, 191) provided thecyclization product, which was catalytically hydrogenated to produce4-acyl-1-(benzyl)piperazin-2-one 5-4.

Scheme 6 illustrates a method for introducing functional groups at the7-position of pyridopyrazine ring subsequent to the preparation of thedihydroxypyridopyrazinedione. As shown in Part A of Scheme 6, halogencan be introduced by treating the dihydroxypyridopyrazinedione 6-1 witha suitable halogenating agent (e.g., Br₂, NBS, ICl, etc). Furtherdescription of this chemistry can be found in March, Advanced OrganicChemistry, 531-534,4th edition. Part B of Scheme 6 shows theintroduction of an alkylamino group via the Mannich reaction, which isdescribed in March, Advanced Organic Chemistry, 900-902, 4th edition. InPart B, dihydroxypyridopyrazinedione 6-1 is treated with a mixture of analdehyde and a nucleophilic secondary amine in an alcoholic solution toprovide the 7-aminoalkylated dihydroxypyridopyrazinedione 6-3.

Scheme 7 depicts a method for preparingdihydroxypyridopyrazine-1,6-diones embraced by Formula (I) of thepresent invention. In Scheme 7, N-(2,2-dimethoxyethyl)-N-alkylamine isacylated with N-acyl-glycine with standard coupling reagents (eg. EDC,BOP, etc). Treatment of the acylation product 7-1 with acid (suitableacids include those disclosed above in the discussion of Scheme 5) willafford 4-acylpyrazin-2-one 7-2, which can be cyclized to providedihydroxypyridopyrazinedione 7-3 via the oxalation-cyclization proceduredepicted in Schemes 1 and 2.

Scheme 8 shows a method for preparingdihydroxydihydropyrido-pyrazine-1,6-diones having an alkyl orsubstituted alkyl at the 4-position of the ring. In Scheme 8, treatmentof alkyl (2-substituted aziridin-1-yl)acetate 8-1 with benzylamine 8-2in the presence of borontrifluoride etherate provided the 5-substituted1-benzylpiperazin-2-one 8-3. Acylation of the piperazinone, followed bythe oxalation-cyclization procedure depicted in Scheme 1 provided the4-substituted dihydroxydihydropyrido-pyrazine-1,6-diones 8-5. Note thatin the case where R⁴′═benzyloxymethyl, compound 8-5 can be hydrogenated(e.g., H₂ over Pd) to afford R⁴′═hydroxymethyl.

Scheme 9 shows a method for preparingdihydroxydihydropyrido-pyrazine-1,6-diones having an aminocarbonylsubstituent at the 4-position of the ring. In Scheme 9, thehydroxymethylpiperazinone 9-1 was oxidized with an oxidizing reagentsuch as Jones reagent. The resulting acid 9-2 was converted to thecorresponding amide 9-3 with coupling reagent such as EDC in thepresence of an amine. Treatment of 9-3 with the oxalation-cyclizationprocedure depicted in Scheme 1 can provide the amide substituteddihydroxydihydropyrido-pyrazine-1,6-diones 9-4.

Scheme 10 depicts a method for preparingdihydroxydihydropyrido-pyrazine-1,6-diones having a heterocyclylmethylsubstituent at the 4-position of the ring. According to Scheme 10, thehydroxymethylpiperazinone 10-1 can be treated with heterocyclicsulfonamides or amide in the presence of coupling reagent such ascyanomethylene tri-n-butylphosphorane ordiethylazodicarboxylate-triphenylphosphine to provide the4-heterocyclic-methyl susbtituted piperazin-2-one 10-2. Treatment of10-2 with the oxalation-cyclization procedure depicted in Scheme 1 canprovide the heterocyclic-methyl susbtituteddihydroxydihydropyrido-pyrazine-1,6-diones 10-3.

Scheme 11 depicts a method for preparing4,5-dihydroxy-tetrahydrocyclopropapyrido-pyrazine-3,7-diones, wherein3,4-dihydropyrazine 11-1 is cyclopropanated with a cyclopropanationreagent such as ethyl diazoacetate and copper bronze. The resultingester 11-2 can be treated with a reducing agent (e.g., sodiumborohydride) to proivee the corresponding alcohol 11-3, which can betreated with an alkylating reagent (e.g., benzyl bromide or an alkylhalide such as methyl iodide) and a base (e.g., NaH) to affordalkylation product 11-4. Subjecting 11-4 to the oxalation-cyclizationprocedure depicted in Scheme 1 can then proivde the desired4,5-dihydroxy-tetrahydrocyclopropapyrido-pyrazine-3,7-dione 11-5.

In the processes for preparing compounds of the present invention setforth in the foregoing schemes, functional groups in various moietiesand substituents may be sensitive or reactive under the reactionconditions employed and/or in the presence of the reagents employed.Such sensitivity/reactivity can interfere with the progress of thedesired reaction to reduce the yield of the desired product, or possiblyeven preclude its formation. Accordingly, it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protective groups may be removed at a convenientsubsequent stage using methods known in the art.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 12-Benzyl-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: Benzyl 4-benzyl-3-oxopiperazine-1-carboxylate

To a cold (0° C.) solution of benzyl 3-oxopiperazine-1-carboxylate (4.7g, 20 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solutionof lithium bis(trimethylsilyl)amide in THF (24 mL, 24 mmol) was addedand stirred at the temperature for 30 min. The resultant solution wastreated with benzyl bromide (2.9 mL, 24 mmol), and stirred at roomtemperature overnight. The product mixture was concentrated undervacuum, and the residue partitioned between aqueous HCl and ethylacetate. The organic extracted was washed with brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith a 50-50 mixture of ethyl acetate and hexane. Collection andconcentration of appropriate fractions provided the benzylated product.

¹H NMR (400 MHz, CDCl₃) δ 7.4-7.2 (m, 10H), 5.15 (s, 2H), 4.63 (s, 2H),4.25 (s, 2H), 3.66 (br t, J=5.3 Hz, 2H), 3.27 (br s, 2H).

ES MS M+1=325

Step 2: 4-Acetyl-1-benzylpiperazin-2-one

A mixture of benzyl 4-benzyl-3-oxopiperazine-1-carboxylate (4.7 g, 14.5mmol) and 10% Pd/C (0.47 g) in ethanol (150 mL) was stirred under anatmosphere of hydrogen (1 atm) at room temperature overnight. Theproduct mixture was filtered through a pad of Celite, and concentratedunder vacuum to provide 1-benzylpiperazin-2-one. A portion of theresultant oil (1.06 g, 5.5 mmol) was treated with a mixture ofN,N-diisopropylethylamine (1.46 mL, 8.3 mmol), DMAP (68 mg, 0.55 mmol),and acetic anhydride (0.73 mL, 7.8 mmol) in methylene chloride (30 mL)at 0° C. After stirring at room temperature overnight, the resultantmixture was concentrated and the residue was subjected to columnchromatography on silica gel eluting with a 10-90 mixture of methanoland ethyl acetate. Collection and concentration of appropriate fractionsprovided the title piperazinone.

¹H NMR (400 MHz, CDCl₃) ˜2:1 mixture of rotomers δ 7.4-7.2 (m, 5H), 4.64(s, 2/3H), 4.63 (s, 1 1/3H), 4.32 (s, 2/3H), 4.21 (s, 1 1/3H), 3.76 (brt, J=5.3 Hz, 1 1/3H), 3.63 (br t, J=5.3 Hz, 2/3H), 3.30 (br t, J=5.3 Hz,2/3H), 3.27 (br t, J=5.3 Hz, 1 1/3H), 2.11 (s, 2H), 2.10 (s, 1H).

ES MS M+1=233

Step 3:2-Benzyl-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a cold (0° C.) solution of 4-acetyl-1-benzylpiperazin-2-one (0.49 g,2.1 mmol) in DMF (10 mL) under an atmosphere of nitrogen, a solution oflithium bis(trimethylsilyl)amide in THF (2.5 mL, 2.5 mmol) was added andstirred at the temperature for 30 min. The resultant solution wastreated with diethyl oxalate (0.43 mL, 3.1 mmol), and stirred at roomtemperature overnight. The resultant mixture was then treated withadditional lithium bis(trimethylsilyl)amide in THF (10 mL, 10 mmol) andstirred at room temperature for 6 h. The product mixture wasconcentrated under vacuum, and the residue partitioned between aqueousHCl and ethyl acetate. The organic extract was dried over anhydrousmagnesium sulfate, filtered, and concentrated under vacuum. The residuewas subjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 11.07 (br s, 1H), 7.39-7.25(m, 5H), 5.93 (s, 1H), 4.70 (s, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.56 (t,J=5.5 Hz, 2H).

ES MS M+1=287

EXAMPLE 22-(4-Fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: N-(2,2-Dimethoxyethyl)-N-(4-fluorobenzyl)amine

A mixture of 4-fluorobenzaldehyde (227.6 g, 1.83 mol) anddimethoxy-ethylamine (192.6 g, 1.83 mol) in methanol (2.5 L) was heatedat 65° C. for 1.5 h. The solution was allowed to cool to roomtemperature overnight and treated with sodium borohydride (47.6 g 1.26mol) in portions over a period of 2 h. The resultant mixture was stirredat room temperature for 3 h and quenched with water (1 L). The productmixture was concentrated to about 1 L and extracted with diethyl ether(3×). The ethereal extracts were combined, washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toprovide the title compound as yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.28 (dd, J=5.5, 8.6 Hz, 2H), 7.00 (t, J=6.8Hz, 2H), 4.48 (t, J=5.5 Hz, 1H), 3.77 (s, 21H), 3.37 (s, 61H), 2.73 (d,J=5.5 Hz, 2H).

ES MS M+1=214

Step 2: N²-acetyl-N¹-(2,2-dimethoxyethyl)-N¹-(4-fluorobenzyl)glycinamide

To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (366.5g, 1.72 mol), N-acetylglycine (213.7 g, 1.83 mol), EDC (350.0 g, 1.83mol), and HOBt (29.1 g, 0.19 mol) in anhydrous DMF (2.5 L),N,N-diisopropylethylamine (˜250 mL) was added until the solution isabout pH 8. The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. The residue was partitionedbetween dichloromethane (4 L) and water (1 L). The organic extract waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) ˜1:1 mixture of rotomers δ 7.27-6.99 (m, 4H),6.57 (br s, 1H), 4.67 (s, 1H), 4.58 (s, 1H), 4.52 (t, J=5.3 Hz, 0.5H),4.32 (t, J=5.3 Hz, 0.5H), 4.20 (d, J=4.0 Hz, 1H), 4.11 (d, J=4.0 Hz,1H), 3.46 (d, J=5.3 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 3H), 3.31 (d, J=5.3Hz, 1H), 2.06 (s, 1.5H), 2.04 (s, 1.5H).

ES MS M-OCH₃=281

Step 3: 4-Acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one

To a solution of methanesulfonic acid (314 g) in dichloromethane (10 L)at room temperature, a solution ofN²-acetyl-N¹-(2,2-dimethoxyethyl)-N¹-(4-fluoro-benzyl)glycinamide (438g, 1.07 mol) in dichloromethane (2 L) was added slowly over a period of2 h. The reaction mixture was stirred at room temperature overnight andtreated with saturated aqueous sodium carbonate (3 L). The organicextract was washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. To the residual oil, ethylacetate (1 L) was added and stirred at room temperature. The solidprecipitated was filtered to provide the title compound.

¹H NMR (400 MHz, CDCl₃) ˜5:1 mixture of rotomers δ 7.3-7.2 (m, 2H),7.1-7.0 (m, 2H), 6.70(d, J=6.4 Hz, 1/5H), 6.11(d, J=6.4 Hz, 4/5H), 5.61(d, J=6.4 Hz, 1/5H), 5.53(d, J=6.4 Hz, 4/5H), 4.68 (s, 1 3/5H), 4.66 (s,2/5H), 4.42 (s, 1 3/5H), 4.36 (s, 2/5H), 2.16 (s, 3H).

ES MS M+1=249

Step 4: 4-Acetyl-1-(4-fluorobenzyl)piperazin-2-one

A mixture of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one(141 g, 0.57 mol) and 5% Pd/C (10.4 g) in ethanol (500 mL) was stirredunder an atmosphere of hydrogen (1 atm) at room temperature overnight.The product mixture was filtered through a pad of Celite, andconcentrated under vacuum to provide the title compound. Residualethanol was removed by co-evaporation with toluene (3×) under vacuum.The resultant oil solidify on standing and was used in the next stepwithout further purification.

¹H NMR (400 MHz, CDCl₃) ˜2:1 mixture of rotomers δ 7.3 (m, 2H), 7.0 (m,2H), 4.58 (s, 2H), 4.32 (s, 2/3H), 4.20 (s, 1 1/3H), 3.77 (br t, J=5.4Hz, 1 1/3 H), 3.63 (br t, J=5.4 Hz,2/3 H), 3.30 (br t, J=5.4 Hz,2/3 H),3.26 (br t, J=5.4 Hz, 1 1/3H), 2.12 (s, 2H), 2.11 (s, 1H).

ES MS M+1=251

Step 5:2-(4-Fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a cold (0° C.) solution of 4-acetyl-1-(4-fluorobenzyl)piperazin-2-one(30.6 g, 122 mmol) in DMF (700 mL) under an atmosphere of nitrogen, asolution of sodium bis(trimethylsilyl)amide in THF (2 M, 73 mL, 146mmol) was added and stirred at the temperature for 30 min. The resultantsolution was treated with diethyl oxalate (16.7 mL, 123 mmol), andstirred at room temperature overnight. The resultant mixture was thentreated with additional sodium bis(trimethylsilyl)amide in THF (2 M, 73mL, 146 mmol) and stirred at room temperature for 4 h. The productmixture was concentrated under vacuum, and the residue treated with amixture of aqueous HCl and ethyl acetate. The resultant precipitate wasobtained by filtration to provide the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H), 11.07 (br s, 1H), 7.40 (dd,J=8.3, 5.8 Hz, 2H), 7.20 (t, J=8.3 Hz, 2H), 5.98 (s, 1H), 4.68 (s, 2H),3.97 (t, J=5.3 Hz, 2H), 3.56 (t, J=5.3 Hz, 2H).

ES MS M+1=305

EXAMPLE 32-(4-Fluorobenzyl)-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 1, except that benzyl bromide (Step 1) wassubstituted with 4-fluorobenzyl bromide, and acetic anhydride (Step 2)was substituted with propionic anhydride.

¹H NMR (400 MHz, CDCl₃) δ 12.50 (s, 1H1), 7.4-7.0 (m, 4H), 6.40 (br s,1H), 4.74 (s, 2H), 4.22 (t, J=5.5 Hz, 2H), 3.55 (t, J=5.5 Hz, 2H), 2.17(s, 3H).

ES MS M+1=319

EXAMPLE 42-(4-Fluorobenzyl)-8,9-dihydroxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a suspension of2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(0.1 g, 0.33 mmol) in chloroform (5 mL), N-bromo-succinimide (64 mg,0.36 mmol) was added and stirred at room temperature overnight. Theproduct mixture was concentrated and the residue was subjected to HPLCpurification on C-18 stationary phase eluted with water/acetonitrile/TFAmobile phase. Collection and lyophilization of appropriate fractionsprovided the title compound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 11.62 (br s, 1H), 7.41 (dd,J=5.8, 8.4 Hz, 2H), 7.20 (t, J=8.8 Hz, 2H), 4.69 (s, 2H), 4.07 (t, J=5.3Hz, 2H), 3.59 (t, J=5.3 Hz, 2H).

ES MS M+1=383/385

EXAMPLE 52-(4-Fluorobenzyl)-8,9-dihydroxy-7-iodo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a suspension of2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(5 g, 16.4 mmol) in methylene chloride (300 mL) at room temperature, asolution of iodine monochloride (2.8 g, 17.2 mmol) in methylene chloride(50 mL) was added. The suspension was stirred at room temperatureovernight and concentrated under vacuum. The residue was dissolved inethyl acetate and washed subsequently with an aqueous solution of sodiummetabisulfite and brine. The organic extract was dried over anhydrousmagnesium sulfate, filtered, concentrated. The residual solid wasstirred in diethyl ether overnight, and collected by filtration.

¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s, 1H), 11.82 (s, 1H), 7.41 (dd,J=6.0, 8.4 Hz, 2H), 7.20 (t, J=8.8 Hz, 2H), 4.69 (s, 2H), 4.07 (t, J=5.3Hz, 2H), 3.59 (t, J=5.3 Hz, 2H).

ES MS M+1=431

EXAMPLE 62-(3-Chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: 4-Acetylpiperazin-2-one

To a cold (0° C.) solution of piperazin-2-one (2.50 g, 24.9 mmol) andN,N-diisopropylethylamine (4.78 mL, 27.5 mmol) in methylene chloride (50mL) under an atmosphere of nitrogen, acetic anhydride (2.47 mL, 26.2mmol) was added and stirred at the temperature for overnight. Theresultant solution was concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with a 90:10:1mixture of chloroform, methanol, and ammonium hydroxide. Collection andconcentration of appropriate fractions provided the title product.

¹H NMR (400 MHz, CDCl₃) ˜2:3 mixture of rotomers δ 6.81 (br s, 2/5H),6.59 (br s, 3/5 H), 4.25 (s, 4/5H), 4.13 (s, 1 1/5 H), 3.82 (t, J=5.4Hz, 11/5 H), 3.67 (t, J=5.4 Hz, 4/5 H), 3.46 (m, 4/5 H), 3.40 (m, 1 1/5H), 2.15 (s, 1H), 2.12 (s, 2H).

ES MS M+1=143

Step 2:2-(3-chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a cold (0° C.) solution of 4-acetylpiperazin-2-one (1.0 g, 7.0 mmol)in DMF (75 mL) under an atmosphere of nitrogen, a solution of lithiumbis(trimethylsilyl)-amide in THF (7.7 mL, 7.7 mmol) was added andstirred at the temperature for 30 min. The resultant solution wastreated with 3-chlorobenzyl bromide (0.92 mL, 7.0 mmol), and stirred atroom temperature overnight. The resultant mixture was cooled to 0° C.,treated with a solution of lithium bis(trimethylsilyl)amide in THF (8.4mL, 8.4 mmol) and stirred for 30 min, and then treated with diethyloxalate (0.96 mL, 7.0 mmol). The resultant mixture was stirred at roomtemperature overnight. Additional solution of lithiumbis(trimethylsilyl)amide in THF (16.8 mL, 16.8 mmol) was added andstirred for 4 hrs. The product mixture was concentrated under vacuum,and the residue was treated with a mixture of aqueous HCl and ethylacetate. The white solid precipitated was collected by filtration andwas subjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 11.07 (br s, 1H), 7.44-7.31(m, 4H), 5.93 (s, 1H), 4.69 (s, 2H), 3.98 (t, J=5.5 Hz, 2H), 3.59 (t,J=5.5 Hz, 2H).

ES MS M+1=322

EXAMPLE 72-(4-Chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 6, except that 3-chlorobenzyl bromide (Step 2) wassubstituted with 4-chlorobenzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 11.10 (br s, 1H), 7.42 (t,J=8.6 Hz, 2H), 7.37 (t, J=8.6 Hz, 2H), 5.94 (s, 1H), 4.68 (s, 2H), 3.97(t, J=6.1 Hz, 2H), 3.57 (t, J=6.1 Hz, 2H).

ES MS M+1=322

EXAMPLE 82-(3,4-Dichlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 6, except that 3-chlorobenzyl bromide (Step 2) wassubstituted with 3,4-dichlorobenzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 11.09 (br s, 1H), 7.65 (d,J=2.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.35 (dd, J=1.8, 8.8 Hz, 1H),5.94 (s, 1H), 4.69 (s, 2H), 3.96 (t, J=5.3 Hz, 2H), 3.59 (t, J=5.3 Hz,2H).

ES MS M+1=356

EXAMPLE 92-(3,4-Difluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 6, except that 3-chlorobenzyl bromide (Step 2) wassubstituted with 3,4-difluorobenzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 11.19 (br s, 1H), 7.48-7.39(m, 2H), 7.23-7.20 (m, 1H), 6.00 (s, 1H), 4.68 (s, 2H), 3.99 (t, J=5.9Hz, 2H), 3.59 (t, J=5.9 Hz, 2H).

ES MS M+1=323

EXAMPLE 102-(3-Chloro-4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 6, except that 3-chlorobenzyl bromide (Step 2) wassubstituted with 3-chloro4-fluorobenzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 11.05 (br s, 1H), 7.60 (d,J=7.0 Hz, 2H), 7.43-7.36 (m, 2H), 5.93 (s, 1H), 4.67 (s, 2H), 3.98 (t,J=5.6 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H).

ES MS M+1=339

EXAMPLE 112-(4-Fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

A mixture of2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(0.2 g, 0.66 mmol), piperidine (0.13 mL, 1.3 mmol), and formaldehyde(0.08 mL, 37% solution in water) in absolute ethanol (5 mL) was stirredat room temperature for 6 h. The product mixture was concentrated undervacuum, and the residue was subjected to HPLC purification on C-18stationary phase eluted with water/acetonitrile/TFA mobile phase.Collection and lyophilization of appropriate fractions provided thetitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 11.91 (s, 1H), 7.41 (dd,J=5.8, 8.4 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.08 (br s,4H), 3.62 (t, J=5.5 Hz, 2H), 3.3 (br s, 2H), 2.9 (br s, 2H), 1.7 (br m,6H).

ES MS M+1=402

EXAMPLE 122-(3-Chloro4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4dihydro-2H-pyrido[1,2-a]pyrazine-1,6dione

The title compound was prepared using a procedure similar to thatdescribed in Example 11, except that2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionewas substituted with2-(3-chloro4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 11.95 (br s, 1H), 7.62 (br d,J=6.9 Hz, 1H), 7.45-7.40 (m, 2H), 4.71 (s, 21), 4.08 (br signal, 4H),3.65 (t, J=5.5 Hz, 2H), 2.96 (br signal, 2H), 2.68 (br s, 2H), 2.33 (brs, 2H), 1.7 (br m, 6H).

ES MS M+1=436

EXAMPLE 132-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(dimethylamino)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 11, except that piperidine was substituted withdimethylamine.

¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 11.90 (br s, 1H), 7.41 (dd,J=6.0, 8.4 Hz, 2H), 7.21 (t, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.22 (s, 2H),4.08 (t, J=5.5 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.74 (s, 6H).

ES MS M+1=362

EXAMPLE 142-(4-Fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione

A mixture of anhydrous DMSO and sodium hydride (0.24 g, 60% oildispersion, washed 3× with hexane) under an atmosphere of nitrogen washeated with stirring at 50° C. for 3 h. After cooling to roomtemperature, a solution of4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (0.5 g, 2.0mmol; Example 2, Step 3) in anhydrous DMSO (5 mL) was added over aperiod of 10 min and the resultant mixture stirred at room temperaturefor 30 min. The mixture was then treated with diethyl oxalate (0.29 mL,2.1 mmol) and stirred at room temperature overnight. The product mixturewas subjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 11.40 (s, 1”), 7.44 (dd,J=5.6, 8.1 Hz, 2H), 7.39 (d, J=6.4 Hz, 1H), 7.21 (t, J=8.1 Hz, 2H), 6.76(d, J=6.4 Hz, 1H), 6.09 (s, 1H), 4.92 (s, 2H).

ES MS M+1=303

The title compound was also prepared as follows:

To a cold (0 C) solution of4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrazin-2(1H)-one (0.41 g, 1.65mmol; Example 2, Step 3) in anhydrous DMF (16 mL) under an atmosphere ofnitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (3.3 mL,3.3 mmol) was added and stirred at that temperature for 15 min. Theresultant solution was treated withN,N′-dimethyloxy-N,N′-dimethyloxalamide (0.29 g, 1.65 mmol; J. Org.Chem. 1995, p. 5016) in one portion, allowed to warm to, and stirred atroom temperature overnight. After 16 hrs. the resultant mixture wastreated with additional lithium bis(trimethylsilyl)amide in THF (1.6 mL,1.6 mmol) and stirred at room temperature for 1 h. The product mixturewas concentrated under vacuum, and the dark brown residue was stirred ina mixture of 1M aqueous hydrochloric acid ( 75 mL) in ice for 15 min.The dark brown solid formed was isolated by filtration and air dried.The dried solid was washed with diethyl ether 2 times, air dried, thendried under vacuum to afford the crude product which was used withoutfurther purification in the preparation of the compound of Example 25.

EXAMPLE 15 2-Benzyl-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using procedures similar to thatdescribed in Examples 2 and 14, except thatN-(2,2-dimethoxyethyl)-N-(4-fluoro-benzyl)amine (Example 2, Step 2) wassubstituted with N-benzylaminoacetaldehyde diethyl acetal.

¹H NMR (400 MHz, CDCl₃) δ 11.95 (s, 1H), 10.56 (br s, 1H), 7.52 (d,J=6.6 Hz, 1H), 7.4-7.3 (m, 5H), 6.33 (s, 1H), 6.22 (d, J=6.6 Hz, 1H),4.92 (s, 2H).

ES MS M+1=285

EXAMPLE 162-(4-Fluorobenzyl)-8,9-dihydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: Ethyl (2-methylaziridin-1-yl)acetate

To a cold (−78° C.) solution of 2-methylaziridine (5.6 g, 99 mmol) andN,N-diisopropylethylamine (18.8 mL, 108 mmol) in dichloromethane (250mL) under an atmosphere of nitrogen, ethyl bromoacetate (10 mL, 90 mmol)was added over a period of 1 h. The resultant mixture was allowed toslowly warm up and stirred at room temperature overnight. The resultantmixture was concentrated under vacuum, and the residue was suspended inchloroform. A stream of anhydrous ammonia gas was bubbled into themixture with stirring for a period of 15 min. The resultant suspensionwas filtered, and the filtrate concentrated under vacuum. The residuewas further treated with anhydrous diethyl ether and the milky solutionfiltered through a pad of Celite. The filtrate was concentrated undervacuum, and the residue subjected to distillation under reduced pressure(bp ˜60° C., 18 torr) to provide the title compound as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 4.21 (q, J=7.1 Hz, 2H), 3.13 (d, J=16.1 Hz,1H), 3.00 (d, J=16.1 Hz, 1H), 1.64 (d, J=3.7 Hz, 1H), 1.47 (m, 1H), 1.33(d, J=6.2 Hz, 1H),1.29 (t, J=7.1 Hz,3H), 1.23 (d, J=5.5 Hz,3H).

Step 2: 4-Acetyl-1-(4-fluorobenzyl)-5-methylpiperazin-2-one

A mixture of ethyl (2-methylaziridin-1-yl)acetate (4.0 g, 28 mmol),4-fluorobenzylamine (5.3 g, 42 mmol), and boron trifluoride etherate(0.5 mL) was heated in a sealed stainless steel vessel inside a Teflonliner at 95° C. for 60 h (Bull. Chem. Soc. Jpn. 1986, 59: 321). Theresulting mixture was dissolved in dichloromethane (50 mL), cooled to 0°C., and treated with a mixture of triethylamine (13 mL, 95 mmol) andacetic anhydride (6.7 mL, 71 mmol). The reaction mixture was stirred atroom temperature overnight, and extracted successively with saturatedaqueous solution of sodium bicarbonate, dilute aqueous HCl, and brine.The organic extract was dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel eluting with a mixture of 7-10 %methanol in ethyl acetate. Collection and concentration of appropriatefractions provided the title piperazinone.

ES MS M+1=265

Step 3:2-(4-Fluorobenzyl)-8,9-dihydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 1 (Step 3), except that4-acetyl-1-benzylpiperazin-2-one was substituted with4-acetyl-1-(4-fluorobenzyl)-5-methylpiperazin-2-one. After the productsolution was concentrated, the residue was treated with a mixture ofdichloromethane and aqueous HCl. The chalky organic extract was isolatedand concentrated under vacuum. The residue was subjected to HPLCpurification on C-18 stationary phase eluted with water/acetonitrile/TFAmobile phase. Collection and lyophilization of appropriate fractionsprovided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 11.04 (br s, 1H), 7.43 (dd,J=8.6, 5.7 Hz, 2H), 7.21 (t, J=8.6 Hz, 2H), 5.92 (s, 1H), 4.83 (d,J=14.5 Hz, 2H), 4.50 (d, J=14.5 Hz, 1H), 3.74 (dd, J=13.2, 4.0 Hz, 1H),3.35 (d, J=14.5 Hz, 1H), 0.98 (d, J=6.0 Hz, 3H).

ES MS M+1=319

EXAMPLE 172-(4-Fluorobenzyl)-8,9-dihydroxy4,4dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: N¹-(4-Fluorobenzyl)-2-methylpropane-1,2-diamine

A mixture of 4-fluorobenzaldehyde (3.1 g, 25 mmol),1,2-diamino-2-methylpropane

(2.2 g, 25 mmol), and a few drop of acetic acid in absolute ethanol (150mL) was stirred at room temperature overnight. The resultant mixture wascooled to 0° C., and treated with sodium borohydride to providepredominately a major mono alkylation product. The reaction mixture wasquenched with trifluoroacetic acid, and concentrated under vacuum. Theresidue was dissolved in methanol and subjected to HPLC purification onC-18 stationary phase eluted with water/acetonitrile/TFA mobile phase.Collection and lyophilization of appropriate fractions provided the TFAsalt of the title compound. This was converted to the corresponding HClsalt by addition of HCl in diethyl ether and concentration under vacuum.The reaction is regioselective and the regiochemistry of the product wasconfirmed with NOE experiments on the bis HCl salt.

¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (br s, 2H), 8.67 (br s, 3H), 7.72 (dd,J=8.4, 5.9 Hz, 2H), 7.29 (t, J=8.8 Hz, 2H), 4.20 (s, 2H), 3.17 (s, 2H),1.39(s, 6H).

Step 2: 1-(4-Fluorobenzyl)-5,5-dimethylpiperazin-2-one

A mixture of N¹-(4-fluorobenzyl)-2-methylpropane-1,2-diamine bishydrochloride salt (0.6 g, 2.23 mmol), N,N-diisopropylethylamine (2 mL,11.5 mmol), and methyl bromoacetate (0.5 mL, 5.3 mmol) indichloromethane (20 mL) was stirred at room temperature overnight toprovide selectively a major alkylation/cyclization product (LC-MS). Theresultant mixture was concentrated under vacuum, treated with asaturated solution of ammonia in chloroform, and filtered through a padof Celite. The filtrate was concentrated and the residue was dissolvedin methanol and subjected to HPLC purification on C-18 stationary phaseeluted with water/acetonitrile/TFA mobile phase. Collection andlyophilization of appropriate fractions provided the TFA salt of thetitle compound. This was converted to the corresponding HCl salt byaddition of HCl in diethyl ether and concentration under vacuum. Thereaction is regioselective and the regiochemistry assigned issubstantiated with subsequent successful acetylation.

¹H NMR (400 MHz, DMSO-d₆) δ 9.80 (br s, 2H), 7.34 (dd, J=8.4, 5.9 Hz,2H), 7.19 (t, J=8.8 Hz, 2H), 4.55 (s, 2H), 3.85 (s, 2H), 3.34 (s, 2H),1.31(s, 6H).

ES MS M+1=237

Step 3:2-(4-Fluorobenzyl)-8,9-dihydroxy4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 1 (Step 2-3), except that 1-benzylpiperazin-2-one(Step 2) was substituted with1-(4-fluorobenzyl)-5,5-dimethylpiperazin-2-one dihydrochloride salt.After the product solution was concentrated, the residue was treatedwith a mixture of dichloromethane and aqueous HCl. The chalky organicextract was isolated and concentrated under vacuum. The residue wassubjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H), 10.95 (br s, 1H), 7.43 (dd,J=8.6, 5.7 Hz, 2H), 7.20 (t, J=8.6 Hz, 2H), 5.82 (s, 1H1), 4.64 (s, 2H),3.23 (s, 2H), 1.45 (s, 2H).

ES MS M+1=333

EXAMPLE 182-(4-Fluorobenzyl)-8,9-dihydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: N-[(tert-Butoxy)carbonyl]-N-(2-oxopropyl)glycine

To a cold (0° C.) solution ofN-[(tert-butoxy)carbonyl]-N-[(methoxy)-(methyl)carbamoylmethyl]glycine(1.0 g, 3.6 mmol; Helvetica Chimica Acta 2000, 83 1825), in anhydrousTHF (30 mL) under an atmosphere of nitrogen, a solution of methylmagnesium bromide in ether (2.6 mL, 3M, 7.8 mmol) was added. Thereaction mixture was stirred at room temperature for 1 h, cooled back to0° C., quenched with aqueous HCl, and diluted with ether. The organicextract was washed with brine (pH adjusted to ˜4-5 with addition ofaqueous sodium hydroxide), dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, DMSO-d₆) ˜1:1 mixture of rotomers δ 4.06 (s, 111), 4.03(s, 1H), 3.88 (s, 1H), 3.84 (s, 1H), 2.05 (s, 3H), 1.36 (s, 9/2H), 1.33(s, 9/2H).

Step 2:4-[(tert-Butoxy)carbonyl]-1-(4-fluorobenzyl)-6-methylpiperazin-2-one

A mixture of N-[(tert-butoxy)carbonyl]-N-(2-oxopropyl)glycine (0.66 g,2.87 mmol), 4-fluorobenzylamine (0.23 g, 1.87 mmol) in dichloroethane(14 mL) was stirred at room temperature for one hour. Sodiumtriacetoxyborohydride (0.79 g, 3.73 mmol) was added and the reactionmixture stirred at room temperature overnight. The resultant mixture wasconcentrated under vacuum. The residue was dissolved in DMF (12 mL),treated with EDC (0.55 g), and stirred at room temperature overnight.The resultant mixture was concentrated under vacuum. The residue waspartitioned between ethyl acetate and dilute aqueous HCl. The organicextract was washed with brine (to pH 7), dried over anhydrous magnesiumsulfate, filtered, and concentrated to provide the title compound.

ES MS M+1=323

Step 3: 4-Acetyl-1-(4-fluorobenzyl)-6-methylpiperazin-2-one

A steady stream of anhydrous HCl gas was bubbled through a cold (0° C.)solution of4-[(tert-butoxy)carbonyl]-1-(4-fluorobenzyl)-6-methylpiperazin-2-one(0.62 g, 1.9 mmol) in ethyl acetate (20 mL) for 5 minutes. The resultantmixture was capped and stirred at the same temperature for 1 h. Theproduct mixture was concentrated under vacuum. The residue was treatedwith a mixture of N,N-diisopropylethylamine (1.00 mL, 5.8 mmol), DMAP (5mg), and acetic anhydride (0.22 mL, 2.3 mmol) in methylene chloride (10mL). The resultant mixture was concentrated and the residue wassubjected to column chromatography on silica gel eluting with a mixtureof 10% methanol in ethyl acetate. Collection and concentration ofappropriate fractions provided the title piperazinone.

¹H NMR (400 MHz, CDCl₃) ˜2:1 mixture of rotomers δ 7.72 (dd, J=8.4, 5.9Hz, 2H), 7.29 (t, J=8.8 Hz, 2H), . . . 2.14 (s, 2H), 2.11 (s, 1H), .1.24(d, J=6.8 Hz, 1H), 1.19 (d, J=6.8 Hz, 2H).

ES MS M+1=265

Step 3:2-(4-Fluorobenzyl)-8,9-dihydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 2 (Step 5), except that4-acetyl-1-(4-fluorobenzyl)piperazin-2-one was substituted with4-acetyl-1-(4-fluorobenzyl)-6-methylpiperazin-2-one. After the productsolution was concentrated, the residue was treated with a mixture ofdichloromethane and aqueous HCl. The chalky organic extract was isolatedand concentrated under vacuum. The residue was subjected to HPLCpurification on C-18 stationary phase eluted with water/acetonitrile/TFAmobile phase. Collection and lyophilization of appropriate fractionsprovided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 10.10 (br s, 1H), 7.43 (dd,J=8.6, 5.7 Hz, 2H), 7.20 (t, J=8.6 Hz, 2H), 5.94 (s, 1H), 4.98 (d,J=15.0 Hz, 1H), 4.40 (d, J=15.0 Hz, 2H), 3.85 (m, 1H), 3.49 (dd, J=14,3.8 Hz, 1H), 1.08 (d, J=6.6 Hz, 3H).

ES MS M+1=319

EXAMPLE 192-(4-Fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-pyrazine-7-carbonitrile

Step 1: 3-[4-(4-Fluorobenzyl)-3-oxopiperazin-1-yl]-3-oxopropanenitrile

To a solution of 1-(4-fluorobenzyl)piperazin-2-one (1.99 g, 9.6 mmol),cyanoacetic acid (0.82 g, 9.6 mmol), EDC (2.02 g, 10.5 mmol), and HOBt(0.15 g, 0.96 mmol) in anhydrous DMF (40 mL), N,N-diisopropylethylaminewas added until the solution is about pH 6. The reaction mixture wasstirred at room temperature overnight and concentrated under vacuum. Theresidue was partitioned between chloroform and water. The organicextract was washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum to provide the title compound.The residue was subjected to column chromatography on silica gel elutingwith a mixture of 9:1:0.1 mixture of chloroform, methanol, and aqammonium hydroxide. Collection and concentration of appropriatefractions provided the title product. Residual protic solvent wasremoved by co-evaporation with benzene (3×). ES MS M-OCH₃=276

Step 2:2-(4-Fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-pyrazine-7-carbonitrile

The title compound was prepared using a procedure similar to thatdescribed in Example 2 (Step 5), except that4-acetyl-1-(4-fluorobenzyl)piperazin-2-one was substituted with3-[4-(4-fluorobenzyl)-3-oxopiperazin-1-yl]-3-oxopropanenitrile. Afterthe product solution was concentrated, the residue was treated with amixture of dichloromethane and aqueous HCl. The chalky organic extractwas isolated and concentrated under vacuum. The residue was subjected toHPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 10.10 (br s, 1H), 7.43 (dd,J=8.6, 5.7 Hz, 2H), 7.20 (t, J=8.6 Hz, 2H), 4.68 (s, 2H),. 3.97 (t,J=5.3 Hz, 2H), 3.56 (t, J=5.3 Hz, 2H).

ES MS M+1=330

EXAMPLE 202-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 11, except that piperidine was substituted with4-methyl-3-oxopiperazine.

¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 11.90 (br s, 1H), 7.41 (dd,J=6.0, 8.4 Hz, 2H), 7.21 (t, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.19 (br s,2H), 4.07 (t, J=5.1 Hz, 2H), 3.78 (br s, 2H), 3.63 (t, J=5.1 Hz, 2H),2.84 (s, 3H).

ES MS M+1=545

EXAMPLE 212-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 11, except that piperidine was substituted with2-oxopiperazine.

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 11.92 (br s, 1H), 8.32 (s,1H), 7.41 (dd, J=6.0, 8.4 Hz, 2H), 7.21 (t, J=8.8 Hz, 2H), 4.71 (s, 2H),4.21 (br s, 2H), 4.07 (t, J=5.1 Hz, 2H), 3.74(br s, 2H), 3.62 (t, J=5.1Hz, 2H), 3.37 (br s, 2H).

ES MS M+1=530

EXAMPLE 224-[(Benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: 2-[(Benzyloxy)methyl]-1-tritylaziridine

To a cold (0° C.) solution of lithium aluminum hydride in diethyl ether(1 M, 15 mL, 15 mmol) under an atmosphere of nitrogen, a solution ofmethyl 1-trityl-2-aziridinecarboxylate (5.04 g, 14.7 mmol) in anhydrousether (60 mL) was added over a period of 0.5 h. The resultant mixturewas allowed to slowly warm up and stirred at room temperature for 1hour. The resultant mixture was cooled back to 0° C. and treatedsuccessively with water (0.57 mL) over a period of 10 minutes, followedby addition of 15% aq NaOH (0.57 mL), and water (1.7 mL). The resultantsuspension was filtered through a pad of Celite. The filtrate was washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was treated with a mixture ofether (40 mL) and hexane (200 mL) with cooling. The precipitate wascollected by filtration to provide (1-tritylaziridin-2-yl)methanol aswhite solid. Without further purification, the alcohol (1.0 g, 3.17mmol) was added portionwise to a suspension of sodium hydride (60%dispersion in mineral oil, 0.24 g, 6.0 mmol). To the resultant mixture,terta-n-butylammonium iodide (50 mg, 0.14 mmol) and benzyl bromide (0.65g, 3.8 mmol) were added. The reaction mixture was stirred at roomtemperature overnight and treated with water (20 mL). The organicextract was diluted with ether, washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with a mixtureof 5% ethyl acetate in hexane. Collection and concentration ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.18 (m, 20 H), 4.52 (s, 2H), 3.86 (dd,J=10.1, 5.1 Hz, 1H), 3.52 (dd, J=10.1, 5.9 Hz, 1H), 1.72 (d, J=3 Hz,1H), 1.54 (m, overlap with H₂O signal), 1.18 (d, J=5.9 Hz, 1H).

ES MS M+1=406

Step 2: Methyl {2-[(benzyloxy)methyl]aziridin-1-yl}acetate

To a cold (0° C.) solution of 2-[(benzyloxy)methyl]-1-tritylaziridine(1.28 g, 3.16 mmol) in dichloromethane (13 mL), trifluoroacetic acid (1mL) and triethylsilane (2.0 mL) was added and stirred at the temperaturefor 1 h. The resultant mixture was concentrated under vacuum, and theresidue was partitioned between ether and brine. The organic extract wasdried with anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with a mixture of 50-100% THF in hexane. Collection andconcentration of appropriate fractions provided2-[(benzyloxy)methyl]aziridine.

To a cold (−78° C.) solution of 2-[(benzyloxy)methyl]aziridine (0.42 g,2.57 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.90 mmol) indichloromethane (15 mL) under an atmosphere of nitrogen, ethylbromoacetate (0.39, 2.5 mmol) was added over a period of 1 h. Theresultant mixture was allowed to slowly warm up to room temperature andstirred overnight. The resultant mixture was washed with brine, driedover anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with a mixture of 70% ethyl acetate in hexane. Collection andconcentration of appropriate fractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.26 (m, 5 H), 4.59 (d, J=11.9 Hz, 1H),4.53 (d, J=11.9 Hz, 1H), 3.74 (s, 3H), 3.52 (m, 2H), 3.25 (d, J=16.1 Hz,1H), 2.98 (d, J=16.1 Hz, 1H), 1.83(d, J=3.6 Hz, 1H), 1.79 (m, 1H), 1.43(d, J=6.4 Hz, 1H).

ES MS M+1=236

Step 3: 4-Acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one

A mixture of methyl {2-[(benzyloxy)methyl]aziridin-1-yl}acetate (0.4 g,1.7 mmol), 4-fluorobenzylamine (0.38 g, 3.3 mmol), and boron trifluorideetherate (50 μL) was heated in a sealed glass tube at 95° C. for 68 h(Bull. Chem. Soc. Jpn., 1986, 59, 321). The resulting mixture wasdissolved in dichloromethane (50 mL), cooled to 0° C., and treated witha mixture of triethylamine (0.95 mL, 6.8 mmol), DMAP (21 mg, 0.17 mmol),and acetic anhydride (0.48 mL, 5.1 mmol). The mixture was stirred atroom temperature overnight, and extracted successively with saturatedaqueous solution of sodium bicarbonate, dilute aqueous HCl, and brine.The organic extract was dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel eluting with a mixture of 2%methanol in ethyl acetate. Collection and concentration of appropriatefractions provided the title piperazinone.

ES MS M+1=371

Step 4:4-[(Benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 1 (Step 3), except that4-acetyl-1-benzylpiperazin-2-one was substituted with4-acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one.

¹H NMR (400 MHz, CDCl₃) δ 12.50 (s, 1H), 8.20 (br s, 1H), 7.33-6.99 (m,9H), 6.14 (s, 1H), 5.09 (m, 1H), 4.75 (d, J=14.6 Hz, 2H), 4.47 (d,J=14.6 Hz, 1H), 4.37 (d, J=11.7, Hz, 1H), 4.25 (d, J=11.7 Hz, 1H), 3.73(d, J=13.2 Hz, 1H), 3.66 (m, 1H), 3.49 (m, 2H), 3.35 (d, J=9.3 Hz, 1H).

ES MS M+1=425

EXAMPLE 234-(Hydroxymethyl)-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

A mixture of4-[(benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(151 mg) and 5% Pd/C (57 mg) in ethanol (20 mL) was stirred under anatmosphere of hydrogen (1 atm) at room temperature overnight. Theproduct mixture was filtered through a pad of Celite, and concentratedunder vacuum. The residue was subjected to HPLC purification on C-18stationary phase eluted with water/acetonitrile/TFA mobile phase.Collection and lyophilization of appropriate fractions provided thetitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 11.10 (s, 1H), 7.41 (dd,J=5.6, 8.6 Hz, 2H), 7.21 (t, J=9.0 Hz, 2H), 5.93 (s, 1H), 5.11 (t, J=5.7Hz, 1H), 4.72-4.60 (m, 2H), 3.69 (br s, 2H).

ES MS M+1=335

EXAMPLE 244-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1:4-Acetyl-5-[(1,1-Dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one

A mixture of4-acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one (6.5 g)and 20% Pd/C (1.4 g) in ethanol (175 mL) was shaken under an atmosphereof hydrogen (60 psi) at room temperature overnight. The product mixturewas filtered through a pad of Celite, and concentrated under vacuum.Residual ethanol was removed by co-evaporation with toluene under vacuum(3×). The resultant alcohol was used without further purification. Amixture of the alcohol (1.0 g, 3.57 mmol), 1,2-thiazinane 1,1-dioxide(0.73, 5.4 mmol), and cyanomethylenetri-n-butylphosphorane (1.3 g, 5.4mmol; [157141-27-0]) in benzene (20 mL) was purged with nitrogen andheated in a sealed tube at 100° C. overnight. The reaction mixture wasconcentrated under vacuum, and the residue was subjected to columnchromatography on silica gel eluting with a mixture of 5% methanol inethyl acetate. Collection and concentration of appropriate fractionsprovided the title compound.

High Resolution FT-ICR M+H=398.1556; C₁₈H₂₄FN₃O₄S+H calculated 398.1545.

Step 2:4-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a cold (0° C.) solution of4-acetyl-5-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one(75 mg, 0.19 mmol) and diethyl oxalate (29 μL, 0.21 mmol) in DMF (3 mL)under an atmosphere of nitrogen, a solution of sodiumbis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added overa period of 0.5 h and stirred at the temperature for 30 min. Thenadditional sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21mmol) was added over a period of 0.5 h and stirred at the temperaturefor 1 h. The product mixture was concentrated under vacuum, and theresidue partitioned between aqueous HCl and ethyl acetate. The organicextract was dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The residue was subjected to HPLCpurification on C-18 stationary phase eluted with water/acetonitrile/TFAmobile phase. Collection and lyophilization of appropriate fractionsprovided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 12.39 (s, 1H), 11.16 (s, 1H), 7.40 (dd, J=8.3,5.8 Hz, 2H), 7.20 (t, J=8.3 Hz, 2H), 5.93 (s, 1H), 5.07 (d, J=14.6 Hz,1H), 4.82 (m, 1H), 4.25 (d, J=14.6 Hz, 1H), 3.68 (dd, J=13.4, 4.4 Hz,1H), 3.56 (d, J=13.5, Hz, 1H), 3.4-2.9 (m), 1.98 (m, 2H), 1.49 (m, 2H).

High Resolution FT-ICR M+H=452.1284; C₂₀H₂₃FN₃O₆S+H calculated 452.1286.

EXAMPLE 252-(4-Fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 11, except that2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionewas substituted with2-(4-fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione(Example 14).

¹H NMR (500 MHz, DMSO-d₆) δ 12.00 (br s, 1H), 9.08 (br s, 1H), 7.50 (d,J=6.3 Hz, 1H), 7.45 (dd, J=8.4, 5.7 Hz, 2H), 7.22 (t, J=8.7 Hz, 2H),6.89 (d, J=6.3 Hz, 1H), 4.97 (s, 2H), 4.15 (s, 2H), 3.6-2.9 (br m),1.8-1.4 (br m).

HRMS FT-ICR m/z obsd 400.1655, C₂₁H₂₂FN₃O₄+H required 400.1667

EXAMPLE 262-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 25, except that piperidine was substituted with3-oxopiperazine.

¹H NMR (500 MHz, DMSO-d₆) δ 12.00 (br s, 1H), 8.28 (s, 1H), 7.49 (d,J=6.6 Hz, 1H), 7.45 (dd, J=8.8, 5.4 Hz, 2H), 7.22 (t, J=8.9 Hz, 2H),6.89 (d, J=6.6 Hz, 1H), 4.97 (s, 2H), 4.24 (s, 2H), 3.72 (s, 2H), 3.35(br s, 4H).

HRMS FT-ICR m/z obsd 415.1406, C₂₀H₁₉FN₄O₅+H required 415.1412.

EXAMPLE 272-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 25, except that piperidine was substituted with4-methyl-3-oxopiperazine.

¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (br s, 1H), 7.49 (d, J=6.5 Hz, 1H),7.45 (dd, J=8.7, 5.6 Hz, 2H), 7.20 (t, J=8.9 Hz, 2H), 6.88 (d, J=6.6 Hz,1H), 4.97 (s, 2H), 4.22 (s, 2H), 3.76 (s, 2H), 3.43(m, 4H), 2.83 (s,3H).

HRMS FT-ICR m/z obsd 429.1562, C₂₁H₂₁FN₄O₅+H required 429.1569.

EXAMPLE 282-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(morpholin4yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 25, except that piperidine was substituted withmorpholine.

¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (br s, 1H), 7.47 (d, J=6.5 Hz, 1H),7.45 (dd, J=8.4, 5.6 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 6.83 (d, J=6.5 Hz,1H), 4.96 (s, 2H), 4.19 (s, 2H), 3.79 (br s, 4H), 3.18(br s, 4H).

HRMS FI-ICR m/z obsd 402.1452, C₂₀H₂₀FN₃O₅+H required 402.1460.

EXAMPLE 292-(4-Fluorobenzyl)-8,9-dihydroxy-7-[(thiomorpholin-4-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 25, except that piperidine was substituted withthiomorpholine.

¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (m, 3H), 7.22 (t, J=8.8 Hz, 2H), 6.79(d, J=6.4 Hz, 1H), 4.94 (s, 2H), 4.16 (s, 2H), 3.35 (br s, 4H), 2.90(brs, 4H).

HRMS FT-ICR m/z obsd 418.1215, C₂₀H₂₀FN₃O₄S+H required 418.1232.

EXAMPLE 302-[4-Fluoro-2-(methylthio)benzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using procedures similar to thatdescribed in Examples 2 and 14, except that 4-fluorobenzaldehyde wassubstituted with 4-fluoro-2-(methylthio)benzaldehyde in Step 1, Example2.

¹H NMR (400 MHz, DMSO-d₆) δ 12.7-12.3 (br signal, 2H), 7.39 (d, J=6.5Hz, 1H), 7.25 (dd, J=8.4, 6.4 Hz, 1H), 7.18 (dd, J=10.4, 2.4 Hz, 1H),6.98 (br t, 1H), 6.53 (d, J=6.5 Hz, 1H), 6.10 (s, 1H), 4.89 (s, 2), 2.54(s, 3H).

HRMS FT-ICR m/z obsd 349.0656, C₁₆H₁₃FN₂O₄S+H required 349.0653

EXAMPLE 317-[(1-Acetylpiperidin-4-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: tert-Butyl4-{3-[4-(4-fluorobenzyl)-3-oxopiperazin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

To a solution of 1-boc-piperidin-4-ylpropionic acid (1.20 g, 4.7 mmol,Astatech) in DMF (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.16 g, 6.1 mmol) and 1-hydroxy-7-azabenzotriazole (0.83g, 6.1 mmol) were added and the solution was stirred at room temperaturefor 30 min. To the resultant solution, a solution of1-(4-fluorobenzyl)piperazin-2-one (1.07 g, 5.1 mmol, see Example 31,Steps 5-8) in DMF (2 mL) was added and the mixture was stirred for twohours. The product mixture was concentrated under vacuum, and theresidue partitioned between water and ethyl acetate. The combinedorganic extracts were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography (ISCO column, 120 g silicagel) eluting with a 0-6% MeOH/CHCl₃ gradient over 40 min. Collection andconcentration of appropriate fractions provided the coupled product as awhite solid.

¹H NMR (400 MHz, d₆ DMSO) δ 7.31 (m, 21), 7.18 (m, 2H), 4.53 (s, 2H),4.19 (s, 1H), 4.07 (s, 1H), 3.91 (m, 2H), 3.67 (m, 2H), 3.31 (m, 2H),3.21 (m, 1H), 2.64 (m, 2H), 2.34 (m, 2H), 1.62 (m, 2H), 1.41 (m, 2H),1.39 (s, 9H), and 0.95 (m, 2H).

ES MS M+1=448

Step 2: tert-Butyl4-{[2-(4-fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl}piperidine-1-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 2 (Step 5) using tert-butyl4-{3-[4-(4-fluorobenzyl)-3-oxo-piperazin-1-yl]-3-oxopropyl}piperidine-1-carboxylate(1.0 g, 2.23 mmol). The crude product was taken on as is to the nextstep.

ES MS M+1=402

Step 3:2-(4-Fluorobenzyl)-8,9-dihydroxy-7-(piperidin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt

To a cold (0° C.) solution of tert-butyl4-{[2-(4-fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl}piperidine-1-carboxylate(1.12 g, 2.23 mmol) in methylene chloride (10 mL), trifluoroacetic acid(3.4 mL, 45 mmol) was added and the mixture was stirred for 2 hours. Themixture was concentrated in vacuo and the residue was purified by prepHPLC (Waters prep LC 4000 System using a Waters Nova Pak column [3*10×40mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.10%TFA)/acetonitrile (0.10% TFA) gradient at 60 mL/min]. Combined andconcentrated the product fractions to give a yellow solid. The solidswere triturated with acetonitrile and collected by vacuum filtration.

¹H NMR (400 MHz, d₆ DMSO) δ 12.61 (s, 1H), 10.42 (s, 1H), 8.41 (m, 1H),8.10 (m, 1H), 7.40 (m, 2H), 7.20 (m, 2H), 4.68 (s, 2H), 4.02 (m, 2H),3.57 (m, 2H), 3.22 (m, 2H), 2.80 (m, 2H), 2.43 (m, 2H), 1.84 (m, 1H),1.67 (m, 2H), and 1.37 (m, 2H),

High Resolution FF-ICR C₂₁H₂₄FN₃O₄+H=402.1833; calculated 402.1824.

Step 4:7-[(1-Acetylpiperidin-4-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a suspension of2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt (50 mg, 0.125 mmol) in anhydrous methylene chloride (2mL), pyridine (12 μL, 0.149 mmol) and acetic anhydride (14 μL, 0.149mmol) were added. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum, and theresidue was purified by prep HPLC (Gilson semi preparative HPLC systemusing a Waters Nova Pak column [10×40 mm I.D. cartridge, C18, 6 μM poresize) eluting with 95-5% water (0.10% TPA)/acetonitrile (0.10% TFA)gradient at 35 mL/min]. Collection and lyophilization of appropriatefractions provided he title compound as white solid.

¹H NMR (400 MHz, d₆ DMSO) δ 12.60 (s, 1H), 10.25 (br s, 1H), 7.40 (m,2H), 7.20 (m, 2H), 4.68 (s, 2H), 4.28 (d, 1H, J=12.9 Hz), 4.03 (m, 2H),3.74 (d, 1H, J=13.2 Hz), 3.58 (m, 2H), 2.91 (m, 1H), 2.42 (m, 3H), 1.96(s, 3H), 1.79 (m, 1H), 1.53 (m, 2H), and 0.96-1.17 (m, 2H).

High Resolution FT-ICR C₂₃H₂₆FN₃O₅+H=444.1929; calculated 444.1929.

Step 5: N-(2,2-Dimethoxyethyl)-N-(4-fluorobenzyl)amine

A mixture of 4-fluorobenzaldehyde (227.6 g, 1.83 mol) anddimethoxy-ethylamine (192.6 g, 1.83 mol) in methanol (2.5 L) was heatedat 65° C. for 1.5 h. The solution was allowed to cool to roomtemperature overnight and treated with sodium borohydride (47.6 g 1.26mol) in portions over a period of 2 h. The resultant mixture was stirredat room temperature for 3 h and quenched with water (1 L). The productmixture was concentrated to about 1 L and extracted with diethyl ether(3×). The ethereal extracts were combined, washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toprovide the title compound as yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.28 (dd, J=5.5, 8.6 Hz, 2H), 7.00 (t, J=6.8Hz, 2H), 4.48 (t, J=5.5 Hz, 1H), 3.77 (s, 2H), 3.37 (s, 6H), 2.73 (d,J=5.5 Hz, 2H).

ES MS M+1=214

Step 6:N²-Benzyloxycarbonyl-N¹-(2,2dimethoxyethyl)-N¹-(4-fluorobenzyl)-glycinamide

To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (50.6 g,237.3 mmol), N—CBZ-glycine (54.6 g, 260.8 mmol), EDC (50.0 g, 260.8mmol), and HOBt (4.2 g, 27 mmol) in anhydrous DMF (500 mL),N,N-diisopropylethylamine (˜10 mL) was added until the solution is aboutpH 7. The reaction mixture was stirred at room temperature overnight andconcentrated under vacuum. The residue was partitioned betweendichloromethane (1 L) and water (250 mL). The organic extract was washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide the title compound.

ES MS M-OCH₃=374

Step 7:4-Benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one

To a solution ofN²-benzyloxycarbonyl-N¹-(2,2-dimethoxyethyl)-N¹-(4-fluorobenzyl)glycinamide(61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) intoluene (450 mL) was stirred at 75° C. for 5 days. Each day anadditional 3 g of toluenesulfonic acids was added. The resultantreaction mixture was cooled to room temperature and filtered through apad of Celite. The filtrate was concentrated under vacuum, and theresidue dissolved in dichloromethane. The organic solution was washedsuccessively with saturated aqueous sodium bicarbonate, brine, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.To the residual solid was subjected to column chromatography on silicagel eluting with dichloromethane and then 5% ethyl acetate indichloromethane. Appropriate fractions were collected and concentratedunder vacuum. Residual ethyl acetate and dichloromethane was removed byco-evaporation with toluene for 3 time for subsequent hydrogenation. Theresidue was triturated with hexane, and filtered to provide thecyclization product as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (br s, 5H), 7.23 (m, 2H), 7.02 (t, J=8.6Hz, 2H), 6.44 (d, J=6.0 Hz, ½H), 6.32 (d, J=6.0 Hz, ½H), 5.53 (d, J=6.0Hz, ½H), 5.42 (d, J=6.0 Hz, ½H), 5.21 (s, 2H), 4.65 (s, 2H), 4.38 (s,2H).

ES MS M+1=341

Step 8: 1-(4-Fluorobenzyl)piperazin-2-one

A mixture of4-benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrazin-2(1H)-one(0.5 g, 14.5 mmol) and Pearlman's catalyst (26 mg; 20% palladiumhydroxide on carbon) in methanol (25 mL) was stirred under an atmosphereof hydrogen (1 atm) at room temperature overnight. The product mixturewas filtered through a pad of Celite, and concentrated under vacuum toprovide 1-(4-fluorobenzyl)piperazin-2-one.

¹H NMR (400 MHz, d₆DMSO) δ 7.29 (dd, J=8.4, 5.7 Hz, 2H), 7.16 (t, J=9.0Hz, 2H), 4.48 (s, 2H), 3.28 (s, 2H), 3.14 (t, J=5.3 Hz, 2H) 2.84 (t,J=5.3 Hz, 2H).

ES MS M+1=209

EXAMPLE 322-(4-Fluorobenzyl)-8,9-dihydroxy-7-{[1-(trifluoroacetyl)piperidin-4-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a solution of2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt [50 mg, 0.125 mmol; Example 31 (Step 3)] in methylenechloride (2 mL), pyridine (12 μL, 0.149 mmol), trifluoroacetic anhydride(26 mg, 0.149 mmol) and a couple drops of DMF were added. After onehour, the reaction mixture was concentrated under vacuum, and theresidue was purified by prep HPLC [Gilson semi preparative HPLC systemusing a Waters Nova Pak column (10×40 mm I.D. cartridge, C18, 6 μM poresize) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA)gradient at 35 mL/min]. The product fractions were collected andlyophilized to provide the title compound as a white solid.

¹H NMR (400 MHz, d₆ DMSO) δ 12.59 (s, 1H), 10.33 (s, 1H), 7.42 (m, 2H),7.20 (m, 2H), 4.69 (s, 2H), 4.23 (m, 1H), 4.03 (m, 2H), 3.82 (m, 1H),3.57 (m, 2H), 3.17 (m, 1H), 2.83 (t, 1H, J=12.3 Hz), 2.44 (m, 2H), 1.91(m, 1H), 1.67 (m, 2H), and 1.17 (m, 2H). High Resolution FT-ICRC₂₃H₂₃F₄N₃O₅+H=498.1655; calculated 498.1647.

EXAMPLE 337-{[1-(Cyclopropylmethyl)piperidin-3-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt

Step 1:2-(4-Fluorobenzyl)-8,9-dihydroxy-7-(piperidin-3-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt

In a manner similar to that described in Example 31 (Step 1 to 3), thetitle compound was prepared as a white solid using1-boc-piperidin-3-ylpropionic acid from Astatech in Step 1.

¹H NMR (400 MHz, d₆ DMSO) δ 12.61 (s, 1H), 10.54 (s, 1H), 8.49 (m, 1H),8.18 (m, 1H), 7.40 (m, 2H), 7.20 (m, 2H), 4.69 (s, 2H), 4.02 (m, 2H),3.57 (m, 2H), 3.17 (d, 1H, J=12.0 Hz), 3.06 (d, 1H, J=12.0 Hz), 2.79 (m,1H), 2.61 (m, 1H), 2.43 (m, 2H), 1.98 (m, 1H), 1.67-1.78 (m, 2H), 1.52(m, 1H), and 1.24 (m, 1H).

High Resolution FT-ICR C₂₁H₂₄FN₃O₄+H=402.1834; calculated 402.1824.

Step 2:7-{[1-(Cyclopropylmethyl)piperidin-3-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt

To a solution of2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-3-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt (50 mg, 0.097 mmol) in anhydrous methanol (2 mL) undernitrogen, cyclopropanecarboxaldehyde (9 μL, 0.116mmol) was added and thesolution was stirred at room temperature for one hour. Sodiumcyanoborohydride (8 mg, 0.129 mmol) was added and the solution wasstirred for another hour. The reaction mixture was concentrated undervacuum and the residue was purified by prep “HPLC [Gilson semipreparative HPLC system using a Waters Nova Pak column (10×40 mm I.D.cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.10%TFA)/acetonitrile (0.10% TFA) gradient at 35 mL/min]. The productfractions were collected and lyophilized to provide the title compoundas white solid.

¹H NMR (400 MHz, d₆ DMSO) δ 12.61 (s, 1H), 10.57 (s, 1H), 9.01 (br s,1H), 7.41 (m, 2H), 7.20 (m, 2H), 4.69 (s, 2H), 4.02 (m, 2H), 3.58 (m,2H), 3.49 (m, 1H), 3.32 (m, 1H), 2.80-2.99 (m, 3H), 2.68 (m, 1H),2.38-2.47 (m, 2H), 2.09 (m, 1H), 1.83 (m, 1H), 1.57-1.70 (m, 2H), 1.17(m,1H), 1.01 (m, 1H), 0.61 (m, 2H), and 0.33 (m, 2H).

High Resolution FT-ICR C₂₅H₃₀FN₃O₄+H=456.2296; calculated 456.2293.

EXAMPLE 347-[(1-Acetylpiperidin-3-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

In a manner similar to that described in Example 31 (Step 4), the titlecompound was prepared as a white solid from2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-3-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt from Example 33 (Step 1).

¹H NMR (400 MHz, d₆ DMSO) δ 12.61 (s, 1H), 10.33 (br s, 1H), 7.40 (m,2H), 7.19 (m, 2H), 4.68 (s, 2H), 4.28 (m, 1H), 4.02 (m, 2H), 3.69 (m,1H), 3.59 (m, 2H), 2.92 (m, 1H), 2.32-2.43 (m, 2H), 2.26 (m, 1H), 1.94(s, 3H), 1.62-1.76 (m, 3H), and 1.13-1.32 (m, 2H). High ResolutionFT-ICR C₂₃H₂₆FN₃O₅+H=444.1911; calculated 444.1929.

EXAMPLE 357-[(1-Acetylpiperidin-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

In a manner similar to that described in Example 31 (Step 1 to 4), thetitle compound was prepared as white solid using1-boc-piperidin-2-ylpropionic acid from Astatech instead of1-boc-piperidin-3-ylpropionic acid in Step 1.

¹H NMR (400 MHz, d₆ DMSO) δ 12.59 (s, 1H), 10.59 (s, 1H), 7.41 (m, 2H),7.19 (m, 2H), 4.68 (s, 2H), 4.23-4.31 (m, 2H), 4.02 (m, 2H), 3.56 (m,2H), 2.91 (m, 1H), 2.67-2.78 (m, 2H), 1.95 (s, 3H), and 1.12-1.87 (m,6H).

High Resolution FT-ICR C₂₃H₂₆FN₃O₅+H=444.1912; calculated 444.1929.

EXAMPLE 367-{[1-(Cyclopropylmethyl)piperidin-2-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionemono TFA salt

In a manner similar to that described in Example 33, the title compoundwas prepared as white solid using 1-boc-piperidin-2-ylpropionic acidfrom Astatech in Step 1.

¹H NMR (400 MHz, d₆ DMSO) δ 12.62 (s, 1H), 10.95 (d, 1H, J=7.7 Hz), 9.22(br s, 1H), 7.41 (m, 2H), 7.20 (m, 2H), 4.69 (s, 2H), 4.03 (m, 2I1),3.57 (m, 2H), 3.03-3.42 (m, 5H), 3.00 (m, 1H), 2.78 (m, 1H), 1.20-1.79(m, 7H), 0.65 (m, 2H), and 0.42 (m, 2H).

High Resolution FT-ICR C₂₅H₃₀FN₃O₄+H=456.2291; calculated 456.2293.

EXAMPLE 372-(3-Cyanobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1: tert-Butyl 4-(3-cyanobenzyl)-3-oxopiperazine-1-carboxylate

To a stirred solution of 4-Boc-2-piperazinone (2.0 g, 10 mmol),3-cyanobenzyl bromide (1.8 g, 10 mmol) in DMF (35 mL) at 0° C. was addedsodium hydride (480 mg of a 60% suspension in mineral oil, 12 mmol) inseveral portions over a period of 15 min. The mixture was stirred a 0°C. for 1 h and then at ambient temperature for 1 h. Acetic acid (1 mL)was added and the solvent was removed in vacuo. The residue waspartitioned between EtOAc and saturated aqueous sodium bicarbonatesolution. The EtOAc layer was separated, dried (MgSO₄), filtered, andthe solvent was removed in vacuo. The residue was triturated in etherand the white solid was collected by filtration to give1-(3-cyanobenzyl)4-Boc-2-piperazinone (2.6 g).

LC-MS m/z=316

Step 2: 3-[(4-Acetyl-2-oxopiperazin-1-yl)methyl]benzonitrile

To a stirred solution of 1-(3-cyanobenzyl)-4-Boc-2-piperazinone (2.5 g,7.9 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added TFA (10 mL). The mixturewas stirred at 0° C. for 2 h, then the solvents were removed in vacuo.The crude 1-(3-cyanobenzyl)-2-piperazinone TFA salt was partitionedbetween EtOAc (30 mL) and saturated aqueous sodium bicarbonate solution(30 mL). To the stirred two-phase mixture was added acetic anhydride(1.5 mL, 15 mmol) dropwise over a period of 5 min. The mixture wasstirred at ambient temperature for 16 h. The EtOAc layer was separated,dried (MgSO₄), filtered, and the solvent was removed in vacuo. Theresidue was purified on a silica gel column using a gradient mobilephase of 2%, 3%, 4% MeOH in CH₂Cl₂.1-(3-cyanobenzyl)-4-acetyl-2-piperazinone was obtained as a solid.

¹H NMR (CDCl₃), 7.4-7.6 ppm (m, 3H), 4.65 (minor) and 4.63 (major) ppm(s, 2H), 4.34 (minor) and 4.23 (major) ppm (s, 2H), 3.81 (major) and3.68 (minor) ppm (t, J=7 Hz, 2H), 3.34 (minor) and 3.30 (major) ppm (t,J=7 Hz, 2H), 2.13 ppm (s, 3H).

LC-MS m/z=258.

Step 3:2-(3-Cyanobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

In a manner similar to that described in Example 1, Step 3, and4-acetyl-1-benzylpiperazin-2-one was substituted with3-[(4-acetyl-2-oxopiperazin-1-yl)methyl]benzonitrile, the title compoundwas prepared.

¹H NMR (400 MHz, CD₃OD) δ 7.77 (s, 1H), 7.72-7.66 (m, 2H), 7.6-7.54 (t,1H), 6.08 (s, 1H), 4.8 (s, 2H), 4.16-4.10 (m, 2H), 3.68-3.62 (m, 2H

EXAMPLE 382-(Biphenyl-3-ylmethyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

Step 1:8,9-Dihydroxy-2-(3-iodobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

To a cold (0° C.) solution of 4-acetyl-1-(3-iodobenzyl)piperazin-2-one(0.22 g, 0.614 mmol) in DMF (5 mL) under an atmosphere of nitrogen, asolution of sodium bis(trimethylsilyl)amide in THF (1 M, 0.74 mL, 0.74mmol) was added and stirred at the temperature for 30 min. The resultantsolution was treated with diethyl oxalate (16.7 mL, 123 mmol), andstirred at room temperature for 30 min. The resultant mixture was thentreated with additional sodium bis(trimethylsilyl)amide in THF (1 M, 2.2mL, 2.2 mmol) and stirred at room temperature overnight. The productmixture was concentrated under vacuum, and the residue treated with amixture of aqueous HCl and ethyl acetate. The resultant precipitate wasobtained by filtration to provide the title compound as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.15(m, 1H), 4.99 (s, 1H), 4.59 (s, 2H), 3.83 (s, 2H), 3.34 (br s, 4H).

ES MS M+1=413

Step 2:2-(1,1′-Biphenyl-3-ylmethyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

A solution of8,9-dihydroxy-2-(3-iodobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(0.05 g, 0.121 mmol) in DMF (5 mL) was degassed for 5 minutes withnitrogen and placed under an atmosphere of nitrogen. To this was addedphenyl boronic acid (0.015 g, 0.123 mmol), triethylamine (0.051 mL,0.364 mmol), and bis(tri-t-butylphosphine)palladium(0) (0.003 g, 0,006mmol) and heated with stirring at 110° C. overnight. The product mixturewas concentrated under vacuum, and the residue was triturated withmethylene chloride. The resultant precipitate was filtered off and thefiltrate concentrated under vacuum. The filtrate residue was subjectedto HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Desired fractions were concentratedunder vacuum to afford the title compound as off white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.6 (m, 4H), 7.42 (m, 3H), 7.32 (m, 2H), 6.07(s, 1H), 4.84 (s, 2H), 4.09 (t, J=5.8 Hz, 2H), 3.63 (t, J=5.8 Hz, 2H).

ES MS M+1=363

EXAMPLE 39(±)-1-[(Benzyloxy)methyl]-2-(4-fluorobenzyl)4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione

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Step 1: (±)-Ethyl5-acetyl-2-(4-fluorobenzyl)-3-oxo-2,5-diazabicyclo[4.1.0]-heptane-7-carboxylate

To a suspension of4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (5.0 g, 20.0mmol; Example 2, Step 3) and copper bronze (320 mg, 5.0 mmol) inanhydrous toluene (50 mL) under nitrogen at 120° C. (oil bath) was addedethyl diazoacetate (6.4 mL, 60.0 mmol) via a syringe pump at a speed of2.5 mL/h. After 3 h, TLC (eluted with ethyl acetate) showed no startingmaterial left. The reaction mixture was cooled to room temperature,filtered and concentrated. The residue was purified by columnchromatography on silica gel using ethyl acetate and methanol as eluentsto give both exo and endo diastereomers.

Exo diastereomer (Rf higher isomer):

¹H NMR (400 MHz, CDCl₃) ˜6:1 mixture of rotomers δ 7.26-7.32 (m, 2H),7.02-7.08 (m, 2H), 4.60-4.83 (m, 3H), 4.10-4.20 (m, 2H), 3.50-3.59 (m,2H), 3.22-3.32 (m, 1H), 2.16 (s, .2.6H), 2.13 (s, 0.4H), 1.63-1.72 (m,1H), 1.27 (q, J=7.2 Hz, 3H).

ES MS M+1=335.3

Endo diastereomer (Rf lower isomer):

¹H NMR (400 MHz, CDCl₃) ˜1:1 mixture of rotomers δ 7.30-7.35 (m, 2H),7.04 (t, J=8.6 Hz, 2H), 4.80-4.98 (m, 1.5H), 4.18-4.36 (m, 1.5H),3.80-4.10 (m, 2.5), 3.56-3.64 (m, 1.5H), 3.28-3.38 (m, 1H), 2.16 (s,.0.5H), 2.13 (s, 0.5H), 2.02-2.06 (m, 1H), 1.14-1.20 (m, 3H).

ES MS M+1=335.3

Step 2:(±)-5-Acetyl-2-(4-fluorobenzyl)-7-(hydroxymethyl)-2,5-diazabicyclo-[4.1.0]heptane-3-one

To a solution of the exo isomer of ethyl5-acetyl-2-(4-fluorobenzyl)-3-oxo-2,5-diazabicyclo[4.1.0]heptane-7-carboxylate(3.3 g, 9.87 mmol) in 32 ml EtOH at room temperature was added sodiumborohydride (398 mg, 10.5 mmol). After stirring overnight, the reactionmixture was treated with 200 mL MeOH, stirred for 1 h and thenconcentrated. The residue was dissolved in dichloromethane (100 mL),treated with 1N HCl (10 mL) and water (20 mL). The aqueous phase wasback extracted with chloroform (2×50 mL). The combined organic phaseswere dried over sodium sulfate, filtered and concentrated. The residuewas purified by column chromatography on silica gel using ethyl acetateand methanol as eluents to give title product.

¹H NMR (400 MHz, CDCl₃) ˜3:2 mixture of rotomers δ 7.26-7.35 (m, 21),7.05 (t, J=8.6 Hz, 2H), 4.42-4.88 (m, 3H), 4.00-4.18 (m, 1H), 3.46-3.76(m, 2.6H), 3.19 (dd, J=10.0, 9.2 Hz, 0.4H), 3.07 (dd, J=7.9, 3.7 Hz,0.6H), 2.92 (dd, J=7.9, 4.0Hz, 0.4H), 2.72-2.80 (m, 1H), 2.21 (s, 1.8H),2.12 (s, 1.2H), 1.16-1.22 (m, 1H).

ES MS M+1=293.3

Step 3:(±)-5-Acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one

To a solution of5-acetyl-2-(4-fluorobenzyl)-7-(hydroxymethyl)-2,5-diazabicyclo[4.1.0]heptane-3-one(1.3 g, 4.45 mmol) in 40 mL anhydrous THF under nitrogen, sodium hydride(60% in mineral oil, 231 mg, 5.78 mmol) was added. After stirring for 1h, benzyl bromide (0.58 ml, 4.89 mmol) in THF (1 mL) was added. Thereaction mixture was stirred at room temperature overnight. The reactionwas quenched with saturated aqueous ammonium chloride solution. Theaqueous layer was extracted with chloroform three times. The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. The residue was purified by column chromatography onsilica gel using hexanes and ethyl acetate as eluents to give the titleproduct.

¹H NMR (400 MHz, CDCl₃) ˜9:1 mixture of rotomers δ 7.22-7.40 (m, 7H),6.99 (t, J=8.6 Hz, 2H), ), 4.94 (d, J=14.1 Hz, 0.1H), 4.83 (d, J=17.1Hz, 0.9H), 4.74 (d, J=14.3 Hz, 0.9H), 4.44-4.50 (m, 2.9H), 4.26 (d,J=14.1 Hz, 0.1H), 4.08 (d, J=16.5 Hz, 0.1H), 3.95 (d, J=16.3 Hz, 0.1H),3.78 (dd, J=10.2, 4.7 Hz, 0.1H), 3.46 (d, J=17.1 Hz, 0.9H), 3.37 (dd,J=10.0, 5.8 Hz, 0.9H), 3.26 (dd, J=10.0, 6.7 Hz, 0.9H), 3.13 (dd,J=10.2, 7.8 Hz, 0.1H), 3.03 (dd, J=7.9, 3.5 Hz, 1H), 2.71 (dd, J=7.9,3.6 Hz, 1H), 2.20 (s, .2.7H), 2.10 (s, 0.3H), 1.16-1.24 (m, 1H).

ES MS M+1=383.3

Step 4:(±)-1-[(Benzyloxy)methyl]-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclopropa[e]pyrido[1,2-a]pyrazine-3,7-dione

To a cold (0° C.) solution of5-acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)-methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one(700 mg, 1.83 mmol) in DMF (10 mL) under nitrogen, a solution of lithiumbis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0 mmol) was added.After 30 min, diethyl oxalate (401 mg, 2.74 mmol) in DMF (2 mL) wasadded. After stirring for 1 h at room temperature, the resultant mixturewas treated with additional lithium bis(trimethylsilyl)amide (1.0 M, 7.1mL, 7.1 mmol), and stirred at room temperature overnight. The reactionmixture was treated with 1 N HCl, concentrated under vacuum. The residuewas partitioned between brine and chloroform. The aqueous layer wasextracted with chloroform twice. The combined organic phases were driedover sodium sulfate, filtered and concentrated. The residue wassubjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, CD₃OD) δ 7.42 (dd, J=8.6, 5.5 Hz, 2H), ), 7.26-7.36 (m,5H), 7.02 (t, J=8.7 Hz, 2H), 6.09 (s, 1H), 4.96 (d, J=14.4 Hz, 1H), 4.69(d, J=14.5 Hz, 1H), 4.48 (s, 2H), 3.81 (dd, J=8.8, 4.6 Hz, 1H), 3.57(dd, J=10.6, 5.3 Hz, 1H), 3.31-3.34 (m, 1H), 3.14 (dd, J=8.8, 4.2 Hz,1H), 1.20-1.25 (m, 1H).

ES MS M+1=437.2

EXAMPLE 40(±)-1-(Methoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 39, except that benzyl bromide was substituted withmethyl iodide in Step 3.

¹H NMR (400 MHz, CDCl₃) δ 7.40 (dd, J=8.6, 5.3 Hz, 2H), ), 7.07 (t,J=8.4 Hz, 2H), 6.25 (s, 1H), 4.81 (d, J=14.3 Hz, 1H), 4.75 (d, J=14.5Hz, 1H), 3.87 (dd, J=8.8, 4.4 Hz, 1H), 3.59 (dd, J=10.6, 5.0 Hz, 1H),3.31 (s, 3H), 3.18 (dd, J=10.6, 7.1 Hz, 1H), 2.98 (dd, J=8.7, 4.2 Hz,1H), 1.12-1.18 (m, 1H).

ES MS M+1=361.2

EXAMPLE 41(±)-1-[(Allyloxy)methyl]-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 39, except that benzyl bromide was substituted withallyl bromide in Step 3.

¹H NMR (400 MHz, CDCl₃) δ 7.40 (dd, J=8.6, 5.1 Hz, 2H), ), 7.06 (t,J=8.6 Hz, 2H), 6.28 (s, 1H), 5.82-5.90 (m, 1H), 5.19-5.28 (m, 2H), 4.81(d, J=14.1 Hz, 1H), 4.75 (d, J=14.1 Hz, 1H), 3.92-3.98 (m, 2H), 3.87(dd, J=8.6, 4.4 Hz, 1H), 3.70 (dd, J=10.6, 4.7Hz, 1H), 3.19 (dd, J=10.6,7.1 Hz, 1H), 2.99 (dd, J=8.6, 4.0 Hz, 1H), 1.12-1.18 (m, 1H).

ES MS M+1=387.2

EXAMPLE 42(±)-1-(Ethoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 39, except that benzyl bromide was substituted withiodoethane in Step 3.

¹H NMR (400 MHz, CDCl₃) δ 13.0 (s, 1H), 7.41 (dd, J=8.0, 5.6 Hz, 21H),), 7.07 (t, J=8.4 Hz, 2H), 6.26 (s, 1H), 4.81 (d, J=14.3 Hz, 1H), 4.77(d, J=14.5 Hz, 1H), 3.86 (dd, J=8.6, 4.4 Hz, 1H), 3.65 (dd, J=10.6, 4.8Hz, 1H), 3.40-3.50 (m, 2H), 3.19 (dd, J=10.6, 7.3 Hz, 1H), 2.99 (dd,J=8.7, 4.1 Hz, 1H), 1.12-1.20 (m, 4H).

ES MS M+1=375.3

EXAMPLE 43(±)-1-(n-Propoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 39, except that benzyl bromide was substituted with1-iodopropane in Step 3.

¹H NMR (400 MHz, CDCl₃) δ 13.0 (s, 1H), 7.41 (dd, J=8.5, 5.3 Hz, 2H), ),7.07 (t, J=8.4 Hz, 2H), 6.24 (s, 1H), 4.81 (d, J=14.3 Hz, 1H), 4.75 (d,J=14.3 Hz, 1H), 3.85 (dd, J=8.4, 4.2 Hz, 1H), 3.68 (dd, J=10.6, 4.5 Hz,1H), 3.30-3.40 (m, 2H), 3.18 (dd, J=10.6, 7.3 Hz, 1H), 2.99 (dd, J=8.6,4.0 Hz, 1H), 1.52-1.60 (m, 2H), 1.15-1.20 (m, 1H), 0.92 (t, J=7.3 Hz,3H).

ES MS M+1=389.3

EXAMPLE 442-[1-(4-Fluorophenyl)ethyl]-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 1, Steps 1 to 3, except that benzyl bromide(Step 1) was substituted with 1-[4-fluorophenyl)-1-bromoethane.

¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 11.05 (br s, 1H), 7.43 (dd,J=8.5, 5.6 Hz, 2H), 7.21 (t, J=8.5 Hz, 2H), 5.92 (s, 1H), 5.80 (q, J=7.1Hz, 1H), 4.05 (m, 1H), 3.74 (m, 1H), 3.54 (m, 1H), 3.15 (m, 1H), 1.55(d, J=7.0 Hz, 3H).

ES MS M+1=319

EXAMPLE 455-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a]quinoxaline-6,10-dione

Step 1: 4-Acetyl-3,4-dihydroquinoxalin-2(1H)-one

To a cold (0° C.) solution of 3,4-dihydroquinoxalin-2(1H)-one (1.0 g,6.7 mmol; J. Med. Chem. 758, 1994) and N,N-diisopropyl-N-ethylamine (1.7mL, 10.1 mmol) in dichloromethane (30 mL) under an atmosphere ofnitrogen, acetic anhydride (0.76 mL, 8.1 mmol) was added and stirred atroom temperature overnight. The resultant solution was concentratedunder vacuum. The residue was subjected to column chromatography onsilica gel eluting with a 1% methanol in chloroform. Collection andconcentration of appropriate fractions provided the acetylation product.

¹H NMR (400 MHz, CDCl₃) δ 10.1 (br s, 1H), 7.23-7.04 (m, 4H), 4.53 (br,s, 2H), 2.28 (br s, 3H).

ES MS M+1=191

Step 2: 4-Acetyl-1-(4-fluorobenzyl)-3,4-dihydroquinoxalin-2(1H)-one

To a cold (0° C.) solution of 4-acetyl-3,4-dihydroquinoxalin-2(1H)-one(0.13 g, 0.68 mmol) in DMF (3.5 mL) under an atmosphere of nitrogen, asolution of lithium bis(trimethylsilyl)amide in THF (0.75 mL, 0.75 mmol)was added and stirred at the temperature for 30 min. The resultantsolution was treated with 4-fluorobenzyl bromide (0.089 mL, 0.72 mmol),and stirred at room temperature for 3 hours. The product mixture wasconcentrated under vacuum, and the residue partitioned between aqueousHCl and ethyl acetate. The organic extract was washed with brine, driedover anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with 50% ethyl acetate in hexane. Collection and concentrationof appropriate fractions provided the title compound.

ES MS M+1=299

Step 3:5-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a]quinoxaline-6,10-dione

To a cold (0° C.) solution of4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-quinoxalin-2(1H)-one (0.15 g,0.52 mmol) in DMF (5 mL) under an atmosphere of nitrogen, a solution oflithium bis(trimethylsilyl)amide in THF (0.57 mL, 0.57 mmol) was addedand stirred at the temperature for 30 min. The resultant solution wastreated with diethyl oxalate (0.078 mL, 0.57 mmol), and stirred at roomtemperature overnight. The resultant mixture was then treated withadditional lithium bis(trimethylsilyl)amide in THF (1.6 mL, 1.6 mmol)and stirred at room temperature for 6 h. The product mixture wasconcentrated under vacuum, and the residue partitioned between aqueousHCl and dichloromethane. The organic extract was dried over anhydrousmagnesium sulfate, filtered, and concentrated under vacuum. The residuewas subjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (s, 1H), 11.53 (br s, 1H), 9.24 (d,J=8.1 Hz, 1H), 7.42 (dd, J=8.2, 5.7 Hz, 2H), 7.20-7.13 (m, 5H), 6.18 (s,1H), 5.36 (s, 2H).

ES MS M+1=353

EXAMPLE 46 5-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:3′,2′-e]pyrazine-6,10-dione

Step 1: N³-(4-Fluorobenzyl)pyridine-2,3-diamine

To a suspension of 2,3-diaminopyridine (3.0 g, 27.5 mmol) and driedmolecular sieves (4 {acute over (Å)}) in THF (230 mL),4-fluorobenzaldehyde (4.56 mL, 42.3 mmol) was added. The resultantmixture was stirred at room temperature overnight, filtered through apad of Celite, and the filtrate concentrated under vacuum. The residuewas subjected to column chromatography on silica gel eluting with a25-100% ethyl acetate in hexane gradient. Collection and concentrationof appropriate fractions provided the imine intermediate. To a cold (0°C.) solution of resultant imine (3.0 g, 13.9 mmol) in anhydrous ethanol(50 mL), sodium borohydride (1.04 g, 28 mmol) was added portionwise. Theresultant solution was stirred at room temperature overnight, andquenched with methanol. The product mixture was concentrated undervacuum, and the residue partitioned between ethyl acetate and water. Theorganic extract was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=4.7 Hz, 1H), 7.33 (dd, J=8.2, 5.8Hz, 2H), 7.04 (br t, J=8.2 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 6.67 (dd,J=7.7, 4.7 Hz, 1H), 4.26 (d, J=4.2 Hz, 2H), 3.56 (br s, 2H).

ES MS M+1=218

Step 2:4-Acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

To a cold (0° C.) solution of N³-(4-fluorobenzyl)pyridine-2,3-diamine(4.4 g, 20.28 mmol) and pyridine (2.5 mL, 31 mmol) in dichloromethane(100 mL) under an atmosphere of nitrogen, chloroacetyl chloride (1.8 mL,22 mol) was added. The resultant solution was stirred at roomtemperature overnight. The product mixture was concentrated undervacuum, and the residue was partitioned between aqueous HCl and ethylacetate. The organic extract was washed with brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under vacuum. The residuewas subjected to column chromatography on silica gel eluting with50-100% ethyl acetate in hexane gradient. Collection and concentrationof appropriate fractions provided the bis chloroacetylated intermediate.ES MS M+1=370.

To a cold (0° C.) solution of the bis chloroacetylation product (120 mg,0.32 mmol) in anhydrous THF (3 mL), a solution of lithiumbis(trimethylsilyl)amide in THF (0.32 mL, 0.32 mmol) was added. Thereaction mixture was stirred at room temperature for a half hour andconcentrated under vacuum. The residue was partitioned between aqueousammonium chloride and ethyl acetate. The organic extract was washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The residue was subjected to columnchromatography on silica gel eluting with an ethyl acetate in hexanegradient. Collection and concentration of appropriate fractions providedthe cyclization intermediate4-chloro-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-oneas white solid.

A mixture of4-chloro-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(2.2 g, 5.96 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was stirredunder an atmosphere of hydrogen (1 atm) at room temperature for 5 hours.The product mixture was filtered through a pad of Celite, andconcentrated under vacuum. The residue was subjected to columnchromatography on silica gel eluting with ethyl acetate and hexane.Collection and concentration of appropriate fractions provided the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=4.8 Hz, 1H), 7.24-7.01 (m, 6H[),5.11 (s, 2H), 4.72 (s, 2H), 2.48 (s, 3H).

ES MS M+1=300

Step 3:5-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:3′,2′-e]pyrazine-6,10-dione

To a cold (0° C.) solution of4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrido[2,3-b]pyrazin-2(1H)-one(0.275 g, 0.903 mmol) in DMF (10 mL) under an atmosphere of nitrogen, asolution of lithium bis(trimethylsilyl)amide in THF (1.44 mL, 1.44 mmol)was added and stirred at the temperature for 30 min. The resultantsolution was treated with dimethyl oxalate (0.21 g, 1.8 mmol), andstirred at room temperature overnight. The resultant mixture was thentreated with additional lithium bis(trimethylsilyl)amide in THF (3.6 mL,3.6 mmol) and stirred at room temperature for 6 h. The product mixturewas concentrated under vacuum, and the residue partitioned betweenaqueous HCl and dichloromethane. The organic extract was dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum.The residue was subjected to HPLC purification on C-18 stationary phaseeluted with water/acetonitrile/TFA mobile phase. Collection andlyophilization of appropriate fractions provided the title compound aswhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=3.7 Hz, 1H), 7.64 (d, J=7.5 Hz,1H), 7.45 (dd, J=8.2, 5.7 Hz, 2H), 7.33 (dd, J=8.2, 4.7 Hz, 1H), 7.18(t, J=8.8 Hz, 2H), 6.10 (s, 1H), 5.32 (s, 2H).

ES MS M+1=354

EXAMPLE 475-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:2′,3′-e]pyrazine-6,10-dione

Step 1: N²-(4-Fluorobenzyl)pyridine-2,3-diamine

A mixture of 2-fluoro-3-nitropyridine (2.5 g, 17.6 mmol),4-fluorobenzyl-amine (4.40 g, 35.2 mmol), andN,N-diisopropyl-N-ethylamine (4.55 g, 35.2 mmol) in anhydrousacetonitrile (30 mL) was stirred at room temperature for 1 hour. Thereaction mixture was concentrated under vacuum, and the residuepartitioned between water and ethyl acetate. The organic extract wasdried over anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with 15% ethyl acetate in hexane. Collection and concentrationof appropriate fractions provided the2-(4-fluorobenzylamino)-3-nitropyridine intermediate as yellow solid.

A mixture of 2-(4-fluorobenzylamino)-3-nitropyridine (1.0 g, 4.05 mmol)and 10% Pd/C (0.3 g) in methanol (50 mL) was stirred under an atmosphereof hydrogen (1 atm) at room temperature for 5 hours. The product mixturewas filtered through a pad of Celite, and concentrated under vacuum. Theresidual methanol was removed by co-evaporation with benzene. Theresultant N²-(4-Fluorobenzyl)pyridine-2,3-diamine was used in thefollowing step without further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=4.7 Hz, 1H), 7.38 (dd, J=8.2, 5.8Hz, 2H), 7.05 (br t, J=8.2 Hz, 2H), 6.88 (d, J=7.7 Hz, 1H), 6.58 (dd, J7.7, 4.7 Hz, 1H), 4.60 (d, J=4.2 Hz, 2), 3.49 (br s,2H).

ES MS M+1=218

Step 2:1-Acetyl-4-(4-fluorobenzyl)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one

The title compound was prepared using a procedure similar to thatdescribed in Example 46, Step 2, except thatN³-(4-luorobenzyl)pyridine-2,3-diamine was substituted withN²-(4-fluorobenzyl)pyridine-2,3-diamine.

Step 3:5-(4-Fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:2′,3′-e]pyrazine-6,10-dione

The title compound was prepared using a procedure similar to thatdescribed in Example 46, Step 3, except that4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrido[2,3-b]pyrazin-2(1H)-onewas substituted with1-acetyl4-(4-fluorobenzyl)-1,4-dihydropyrido[2,3-b]pyrazin-3 (2H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 11.65 (br s, 1H), 9.72 (d,J=8.6 Hz, 1H), 8.22 (d, J=4.0 Hz, 1H), 7.44 (dd, J=8.2, 5.7 Hz, 2H),7.25 (m, 1H), 7.11 )t, J=8.8 Hz, 2H), 6.17 (s, 1H), 5.44 (s, 2H).

ES MS M+1=354

EXAMPLE 48

Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule. Encapsulated oral compositionscontaining any one of the compounds of Examples 2-47 can be similarlyprepared.

EXAMPLE 49

HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase

Assays for the strand transfer activity of integrase were conducted inaccordance with WO 02/30930 for recombinant integrase. Representativecompounds of the present invention exhibit inhibition of strand transferactivity in this assay. For example, the compounds prepared in Examples1-47 were tested in the integrase assay and all were found to haveIC₅₀'s less than 5 micromolar, and all but the compounds prepared inExamples 37, 38 and 44 were found to have ICIC₅₀'s less than 0.5micromolar.

Further description on conducting the assay using preassembled complexesis found in Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, Hazudaet al., J. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design andDiscovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287:646-650.

EXAMPLE 50

Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., Proc. Natl. Acad.Sci. USA 1994, 91: 4096. Representative compounds of the presentinvention exhibit inhibition of HIV replication in this assay. Forexample, the compounds prepared in Examples 1-47 were tested in thepresent assay and all were found to have IC₉₅'s less than 10 micromolar.In particular, the compounds of Examples 1-18 were found to have IC₉₅'sless than 5 micromolar, and the compounds of Examples 2, 6, 8-12, 14,15, 25, 27-30, 34, 35, 42 and 43 were found to have IC₉₅'s less than 1micromolar.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A compound of Formula (I), or a pharmaceutically acceptable saltthereof:

wherein R¹ is C₁₋₆ alkyl which is substituted with 1 or 2 substituentseach of which is independently: (1) C₃₋₈ cycloalkyl, (2) aryl, (3) a 5-or 6-membered saturated or mono-unsaturated heterocyclic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S, (4) a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, or (5) a 9- or 10-membered fusedbicyclic heterocycle containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein at least one of the rings is aromatic;wherein (A) each cycloalkyl is optionally substituted with from 1 to 3substituents, each of which is independently halo, —C₁₋₆ alkyl, or—O—C₁₋₆ alkyl; (B) each aryl is optionally substituted with from 1 to 5substituents each of which is independently (1) —C₁₋₆ alkyl, optionallysubstituted with from 1 to 3 substituents each of which is independently—OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₆ alkyl, optionally substitutedwith from 1 to 3 substituents each of which is independently —OH,—O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₆ haloalkyl, (4) —O—C₁₋₆ haloalkyl,(5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10)—C(═O)N(R^(a)R^(b)), (11) —C(═O)R^(a), (12) —CO₂R^(c), (13) —SR^(c),(14) —S(═O)R^(c), (15) —SO₂R^(c), (16) —N(R^(a))SO₂R^(c), (17)—SO₂N(R^(a)R^(b)), (18) —N(R^(a))C(═O)R^(b), (19) —NR^(a))CO₂R^(c), or(20) phenyl; (C) each saturated or mono-unsaturated heterocyclic ring is(i) optionally substituted with from 1 to 5 substituents each of whichis independently halogen, —C₁₋₆ alkyl, -C₁₋₆ haloalkyl, —O—₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2substituents each of which is independently aryl or a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; and (D) each heteroaromatic ring or each fusedbicyclic heterocycle is (i) optionally substituted with from 1 to 7substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and (ii) optionallysubstituted with 1 or 2 substituents each of which is independently arylor —C₁₋₆ alkyl-aryl; R² is —H or —C₁₋₆ alkyl; R³ is —H, —C₁₋₆ alkyl,—C₁₋₆ haloalkyl, or —C₁₋₆ alkyl substituted with one of —OH, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)); R⁴ is: (1) —H, (2) —C₁₋₆ alkyl optionallysubstituted with one of —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN,—NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c),—S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O,—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),—N(R^(a))C(═O)N(R^(a)R^(b)), —O—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), —S—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), or—N(SO₂R^(c))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), (3) —C₁₋₆ haloalkyl, (4)—C(═O)R^(a), (5) —CO₂R^(c), (6) —C(═O)N(R^(a)R^(b)), (7)—SO₂N(R^(a)R^(b)), (8) —C₂₋₆ alkenyl, (9) —C₂₋₆ alkenyl-C(═O)—N(R^(a))₂,(10) —C₂₋₅ alkynyl, (11) —C₂₋₅ alkynyl-CH₂N(R^(a))₂, (12) —C₂₋₅alkynyl-CH₂OR^(a), (13) —C₂₋₅ alkynyl-CH₂S(O)_(n)R^(c), or (14) —R^(k),(15) —C₁₋₆ alkyl substituted with R^(k), (16) —C₁₋₆ haloalkylsubstituted with R^(k), (17) —C₁₋₆ alkyl-O—R^(k), (18) —C₁₋₆alkyl-O—C₁₋₆ alkyl-R^(k), (19) —C₁₋₆ alkyl-S(O)_(n)—R^(k), (20) —C₁₋₆alkyl-S(O)_(n—C) ₁₋₆ alkyl-R^(k), (21) —C₁₋₆ alkyl—N(R^(a))—R^(k), (22)—C₁₋₆ alkyl—N(R^(a))—C₁₋₆ alkyl-R^(k), (23) —C₁₋₆ alkyl—N(R^(a))—C₁₋₆alkyl-OR^(k), with the proviso that the —N(R^(a))— moiety and the—OR^(k) moiety are not both attached to the same carbon of the —C₁₋₆alkyl-moiety, (24) —C₁₋₆ alkyl-C(═O)—R^(k), (25) —C₁₋₆alkyl-C(═O)N(R^(a))—R^(k), (26) —C₁₋₆ alkyl—N(R^(a))C(═O)—R^(k), (27)—C₁₋₆ alkyl-C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k), or (28) —C₁₋₆alkyl—N(R^(a))—CO₁₋₆ alkyl-S(O)_(n)R^(k); wherein R^(k) is (i) aryl,which is optionally substituted with from 1 to 5 substituents each ofwhich is independently —C₁₋₆ alkyl, —C₁₋₆ alkyl-OH, —C₁₋₆ alkyl-O—C₁₋₆alkyl, —C₁₋₆ alkyl-O—C₁₋₆ haloalkyl, —C₁₋₆ alkyl-N(R^(a)R^(b)), —C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(═O)R^(a), —C₁₋₆ alkyl-CO₂R^(c),—C₁₋₆ alkyl—S(O)_(n)R^(c), —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, —OH, halo, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),—CO₂R^(c), —S(O)_(n)R^(c), or —SO₂N(R^(a)R^(b)); (ii) a 4- to 7-memberedsaturated or mono-unsaturated heterocyclic ring containing at least onecarbon atom and from 1 to 4 heteroatoms independently selected from N, Oand S, wherein the heterocyclic ring is: (a) optionally substituted withfrom 1 to 5 substituents each of which is independently halogen, —C₁₋₆alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and(b) optionally mono-substituted with aryl or HetA;  wherein HetA is a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally fused with a benzene ring, and HetA is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;or (iii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;or alternatively R³ and R⁴ are joined together to form C₅₋₈ cycloalkylor a 5- to 7-membered saturated heterocyclic ring containing from 1 to 4heteroatoms independently selected from N, O and S; wherein thecycloalkyl is optionally substituted with from 1 to 3 substituents eachof which is independently halo, —C₁₋₆ alkyl, or —O—C₁₋₆ alkyl; and theheterocyclic ring is optionally substituted with from 1 to 4substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; or alternatively:(i) R² and R³ together form a direct bond to give a ring double bond,and R⁴ is an independent group as defined above; (ii) R² and R³ togetherwith the ring carbon atoms to which they are attached form a fusedcyclopropyl ring which is optionally substituted at the non-fusedcyclopropyl ring carbon with —OR^(d), and R⁴ is —H; or (iii) R² and R³together with the ring carbon atoms to which they are attached form afused phenyl ring or a fused pyridyl ring, and R⁴ is absent; R⁵ is: (1)—H, (2) —C₁₋₆ alkyl, (3) —C₁₋₆ alkyl-N(R^(a)R^(b)), (4) —₁₋₆alkyl-C(═O)N(R^(a)R^(b)), (5) —C₁₋₆ alkyl-C(═O)R^(a), (6) —C₁₋₆alkyl—CO₂R^(c), (7) —C₁₋₆ alkyl-SR^(c), (8) —C₁₋₆ alkyl—S(═O)R^(c), (9)—C₁₋₆ alkyl-SO₂R^(c), (10) —C₁₋₆ alkyl-SO₂N(R^(a)R^(b)) (11) —C₁₋₆haloalkyl, (12) —O—C₁₋₆ alkyl, (13) —O—C₁₋₆ haloalkyl, (14) halo, (15)—CN, (16) —C(═O)R^(a), (17) —CO₂R^(c), (18) —SR^(c), (19) —S(═O)R^(c),(20) —SO₂R^(c), (21) —N(R^(a)R^(b)), (22) —C(═O)N(R^(a)R^(b)), or (23)—SO₂N(R^(a)R^(b)); (24) aryl (25) —₁₋₆ alkyl-aryl (26) HetB, (27) —₁₋₆alkyl-HetB, (28) HetC, or (29) —₁₋₆ alkyl-HetC, wherein HetB is a 5- or6-membered saturated or mono-unsaturated ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein the ring isoptionally substituted with from 1 to 5 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, oxo, —C(═O)—C₁₋₆ alkyl, —C(═O)—C₁₋₆ haloalkyl, or—C₁₋₆ alkyl-C₃₋₈ cycloalkyl; and HetC is a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;each R^(a) and R^(b) is independently —H or —C₁₋₆ alkyl; each R^(c) isindependently a —C₁₋₆ alkyl; R^(d) is a —C₁₋₆ alkyl, allyl, or benzyl;and each n is independently an integer equal to 0, 1 or
 2. 2. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is —C₁₋₄ alkyl mono-substituted with aryl; whereinthe aryl is optionally substituted with from 1 to 4 substituents each ofwhich is independently (1) —C₁₋₄ alkyl, optionally mono-substituted with—OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₄ alkyl, optionallymono-substituted with —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,—S(O)_(n)R^(c), —N(R^(a))—CO₂R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl,(5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10) —SR^(c),(11) —S(═O)R^(c), (12) —SO₂R^(c), (13) —N(R^(a))SO₂R^(c), (14)—SO₂N(R^(a)R^(b)), (15) —N(R^(a))C(═O)R^(b), (16) —N(R^(a))CO₂R^(c), or(17) phenyl.
 3. The compound according to claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is —(CH₂)₁₋₄-phenyl, wherein thephenyl is optionally substituted with from 1 to 3 substituents each ofwhich is independently (1) —C₁₋₄ alkyl, optionally mono-substituted with—OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), or—SO₂N(R^(a)R^(b)), (2) —O—C₁₋₄ alkyl, (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄haloalkyl, (5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)),(10) —SR^(c), (11) —S(═O)R^(c), (12) —SO₂R^(c), (13) —N(R^(a))SO₂R^(c),(14) —SO₂N(R^(a)R^(b)), (15) —N(R^(a))C(═O)R^(b), (16)—N(R^(a))CO₂R^(c), or (17) phenyl.
 4. The compound according to claim 3,or a pharmaceutically acceptable salt thereof, wherein R¹ is:

wherein X¹ and X² are each independently (1) —H, (2) methyl, (3) ethyl,(4) methoxy, (5) ethoxy, (6) —CF₃, (7) fluoro, (8) bromo, (9) chloro,(10) —CN, (11) —S—CH₃, or (12) phenyl.
 5. The compound according toclaim 4, or a pharmaceutically acceptable salt thereof, wherein R¹ is4-fluorobenzyl.
 6. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R² is —H or —C₁₋₄alkyl; R³ is —H or —C₁₋₄ alkyl; and R⁴ is: (1) —H, (2) —C₁₋₄ alkyloptionally substituted with one of —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),—CO₂R^(c), —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O,—N(R^(a))SO₂R^(b), or —N(R^(a))SO₂N(R^(a)R^(b)), (3)—C(═O)N(R^(a)R^(b)), (4) —R^(k), (5) —C₁₋₄ alkyl substituted with R^(k),(6) —C₁₋₄ alkyl-O—R^(k), or (7) —C₁₋₄ alkyl-O—C₁₋₄ alkyl-R^(k).
 7. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₁₋₄alkyl-N(R^(a)R^(b)), (4) —C₁₋₄ alkyl-C(═O)N(R^(a)R^(b)), (5) —C₁₋₄alkyl—SO₂N(R^(a)R^(b)) (6) —C₁₋₄ haloalkyl, (7) halo, (8) —CN, (9) aryl(10) —C₁₋₄ alkyl-aryl (11) HetB, (12) —C₁₋₄ alkyl-HetB, (13) HetC, or(14) —C₁₋₄ alkyl-HetC, wherein HetB is a 5- or 6-membered saturated ringcontaining a total of from 1 to 4 heteroatoms independently selectedfrom 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms,wherein the saturated ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo, —C(═O)—C₁₋₄ alkyl,—C(═O)—C₁₋₄ haloalkyl, or —C₁₋₄ alkyl-C₃₋₆ cycloalkyl; and HetC is a 5-or 6-membered heteroaromatic ring containing a total of from 1 to 4heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 Oatoms, and from 0 to 2 S atoms, wherein the heteroaromatic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or oxo.
 8. The compound according to claim 7, or apharmaceutically acceptable salt thereof, wherein R⁵ is: (1) —H, (2)—C₁₋₄ alkyl, (3) —C₁₋₄ alkyl-N(R^(a)R^(b)), (4) halo, (5) —CN, or (6)—C₁₋₄ alkyl-HetB; wherein HetB is a 5- or 6-membered saturated ringcontaining 1 or 2 N atoms and carbon atoms, wherein the saturated ringis optionally substituted with from 1 to 4 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,—O—C₁₋₄ haloalkyl, oxo, —C(═O)—C₁₋₄ alkyl, —C(═O)—C₁₋₄ haloalkyl, or—C₁₋₄ alkyl-C₃₋₆ cycloalkyl.
 9. A compound of Formula (II), or apharmaceutically acceptable salt thereof:

wherein: X¹′ and X²′ are each independently: (1) —H, (2) C₁₋₄ alkyl, (2)—O—C₁₋₄ alkyl, (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl, (5) halo, (6)—CN, (7) —S—C₁₋₄ alkyl, or (8) phenyl; R²′ is —H or —C₁₋₄ alkyl; R³′ is—H or —C₁₋₄ alkyl; R⁴′ is: (1) —H, (2) —C₁₋₄ alkyl optionallysubstituted with one of —OH, —N(R^(a)′R^(b)′), or —C(═O)N(R^(a)′R^(b)′),(3) —C(═O)N(R^(a)′R^(b)′), (4) —(CH₂)₁₋₃—R^(k), (5) —(CH₂)₁₋₃—O—R^(k)′,or (6) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k); wherein R^(k)′ is: (i) phenyl, whichis optionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄haloalkyl, or halo; or (ii) HetD, wherein HetD is a 5- or 6-memberedsaturated ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a balanceof carbon atoms, wherein the saturated ring is optionally substitutedwith from 1 to 4 substituents each of which is independently halo, —C₁₋₄alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; oralternatively: (i) R²′ and R³′ together form a direct bond to give aring double bond, and R⁴′ is an independent group as defined above; (ii)R²′ and R³′ together with the ring carbon atoms to which they areattached form a fused cyclopropyl ring which is optionally substitutedat the non-fused cyclopropyl ring carbon with —OR^(d)′, and R⁴′ is —H;or (iii) R²′ and R³′ together with the ring carbon atoms to which theyare attached form a fused phenyl ring or a fused pyridyl ring, and R⁴′is absent; R⁵′ is: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₁₋₄alkyl-N(R^(a)′R^(b)′), (4) halo, (5) —CN, or (6) —(CH₂)₁₋₃-HetB; whereinHetB is a 5- or 6-membered saturated ring containing 1 or 2 N atoms,zero or 1 O atom, zero or 1 S atom, and a balance of carbon atoms,wherein the saturated ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo, —C(═O)—C₁₋₄ alkyl,—C(═O)—C₁₋₄ haloalkyl, or —C₁₋₄ alkyl-C₃₋₆ cycloalkyl; R⁶′ is —H ormethyl; each R^(a)′ and R^(b)′ is independently —H or —C₁₋₄ alkyl; andR^(d)′ is —C₁₋₄ alkyl, allyl, or benzyl.
 10. A compound according toclaim 9, or a pharmaceutically acceptable salt thereof, wherein: whereinX¹′ and X²′ are each independently: (1) —H, (2) methyl, (2) —OCH₃, (3)—CF₃, (4) —O—CF₃, (5) chloro, (6) fluoro, (7) bromo; (6) —CN, (7)—S—CH₃, or (8) phenyl; R²′ is —H or methyl; R³′ is —H or methyl; R⁴′ is:(1) —H, (2) methyl, (3) —CH₂OH, (3) —C(═O)N(CH₃)₂, (4) —CH₂—R^(k)′, or(5) —CH₂—O—CH₂—R^(k)′; wherein R^(k)′ is: (i) phenyl, which isoptionally substituted with from 1 to 3 substituents each of which isindependently —CH₃, —OCH₃, —CF₃, —OCF₃, chloro, bromo or fluoro; or (ii)HetD, wherein HetD is a 5- or 6-membered saturated ring containing 1 or2 N atoms, 0 or 1 S atoms, and a balance of carbon atoms, wherein thesaturated ring is optionally substituted with from 1 to 4 substituentseach of which is independently chloro, bromo, fluoro, —CH₃, —CF₃, —OCH₃,—OCF₃, or oxo; or alternatively: (i) R²′ and R³′ together form a directbond to give a ring double bond, and R⁴′ is an independent group asdefined above; (ii) R²′ and R³′ together with the ring carbon atoms towhich they are attached form a fused cyclopropyl ring which isoptionally substituted at the non-fused cyclopropyl ring carbon with—OMe, —OEt, —O-allyl, or —O-benzyl, and R⁴ is —H; or (iii) R²′ and R³′together with the ring carbon atoms to which they are attached form afused phenyl ring or a fused pyridyl ring, and R⁴′ is absent; R⁵′ is:(1) —H, (2) methyl, (3) —(CH₂)₁₋₂—N(CH₃)₂, (4) fluoro, (5) bromo, (6)iodo, (7) —CN, or (8) —CH₂-HetB; wherein HetB is a 5- or 6-memberedsaturated ring containing 1 or 2 N atoms, zero or 1 O atom, zero or 1 Satom, and a balance of carbon atoms, wherein the saturated ring isoptionally substituted with from 1 to 4 substituents each of which isindependently chloro, bromo, fluoro, —CH₃, —CF₃, —OCH₃, —OCF₃, oxo,—C(═O)—CH₃, —C(═O)—CF₃, or —CH₂-cyclopropyl; and R⁶′ is —H or methyl.11. The compound according to claim 9, which is a compound of Formula(IIa), or a pharmaceutically acceptable salt thereof:

wherein: X¹′ and X²′ are each independently: (1) —H, (2) C₁₋₄ alkyl, (2)—O—C₁₋₄ alkyl, (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl, or (5) halo;R²′ is —H or —C₁₋₄ alkyl; R³′ is —H or —C₁₋₄ alkyl; or alternatively R²′and R³′ together form a direct bond to give a ring double bond; R⁴′ is:(1) —H, (2) —C₁₋₄ alkyl optionally substituted with one of —OH,—N(R^(a)′R^(b)′), or —C(═O)N(R^(a)′R^(b)′), (3) —C(═O)N(R^(a)′R^(b)′),(4) —(CH₂)₁₋₃—R^(k)′, (5) —(CH₂)₁₋₃—O—R^(k)′, or (6)—(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k)′; wherein R^(k)′ is: (i) phenyl, which isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄haloalkyl, or halo; or (ii) HetD, wherein HetD is a 5- or 6-memberedsaturated ring containing 1 or 2 N atoms, 0 or 1 S atoms, and a balanceof carbon atoms, wherein the saturated ring is optionally substitutedwith from 1 to 4 substituents each of which is independently halo, —C₁₋₄alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; R⁵′is: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₁₋₄ alkyl-N(R^(a)′R^(b)′), (4) halo,(5) —CN, or (6) —(CH₂)₁₋₃-HetB; wherein HetB is a 5- or 6-memberedsaturated ring containing 1 or 2 N atoms and carbon atoms, wherein thesaturated ring is optionally substituted with from 1 to 4 substituentseach of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; and each R^(a)′ and R^(b)′ isindependently —H or —C₁₋₄ alkyl.
 12. The compound according to claim 9,which is a compound of Formula (III), or a pharmaceutically acceptablesalt thereof:

wherein: X¹′ and X²′ are each independently —H or halo.
 13. The compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof,wherein X¹′ and X²′ are each independently —H, fluoro, chloro, or bromo;R²′ is —H or methyl; R³′ is —H or methyl; R⁴′ is: (1) —H, (2) methyl,(3) —CH₂OH, (3) —C(═O)N(CH₃)₂, (4) —CH₂—R^(k)′, or (5)—CH₂—O—CH₂—R^(k)′; wherein R^(k′ is:) (i) phenyl, which is optionallysubstituted with from 1 to 3 substituents each of which is independently—CH₃, —OCH₃, —CF₃, —OCF₃, chloro, bromo or fluoro; or (ii) HetD, whereinHetD is a 5- or 6-membered saturated ring containing 1 or 2 N atoms, 0or 1 S atoms, and a balance of carbon atoms, wherein the saturated ringis optionally substituted with from 1 to 4 substituents each of which isindependently chloro, bromo, fluoro, —CH₃, —CF₃, —OCH₃, —OCF₃, or oxo;and or alternatively: (i) R²′ and R³′ together form a direct bond togive a ring double bond, and R⁴′ is an independent group as definedabove; (ii) R²′ and R³′ together with the ring carbon atoms to whichthey are attached form a fused cyclopropyl ring which is optionallysubstituted at the non-fused cyclopropyl ring carbon with —OR^(d)′, andR⁴′ is —H; or (iii) R²′ and R³′ together with the ring carbon atoms towhich they are attached form a fused phenyl ring or a fused pyridylring, and R⁴′ is absent; R⁵′ is: (1) —H, (2) methyl, (3)—(CH₂)₁₋₂—N(CH₃)₂, (4) fluoro, (5) bromo, (6) iodo, (7) —CN, or (8)—CH₂-HetB; wherein HetB is a 5- or 6-membered saturated ring containing1 or 2 N atoms, zero or 1 O atom, zero or 1 S atom, and a balance ofcarbon atoms, wherein the saturated ring is optionally substituted withfrom 1 to 4 substituents each of which is independently chloro, bromo,fluoro, —CH₃, —CF₃, —OCH₃, —OCF₃, oxo, —C(═O)—CH₃, —C(═O)—CF₃, or—CH₂-cyclopropyl.
 14. The compound according to claim 13, or apharmaceutically acceptable salt thereof, wherein X¹′ is fluoro and X²′is —H.
 15. A compound selected from the group consisting of:2-benzyl-8,9-dihydroxy-3,4-dihydro-2H-pyrido [1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-iodo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(3-chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-chlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione2-(3,4-dichlorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(3,4-difluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione2-(3-chloro-4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(3-chloro-4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(dimethylamino)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione2-benzyl-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione2-(4-fluorobenzyl)-8,9-dihydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]-pyrazine-7-carbonitrile;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;4-[(benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;4-(hydroxymethyl)-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;4-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-1-ylmethyl)-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(4-methyl-3-oxopiperazin-1-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(morpholin4-yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-[(thiomorpholin4yl)methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-[4-fluoro-2-(methylthio)benzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione;7-[(1-acetylpiperidin-4-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(4-fluorobenzyl)-8,9-dihydroxy-7-{[1-(trifluoroacetyl)piperidin-4-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;7-{[1-(cyclopropylmethyl)piperidin-3-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;7-[(1-acetylpiperidin-3-yl)methyl]-2-(4-fluorobenzyl)-8,9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;7-[(1-acetylpiperidin-2-yl)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;7-{[1-(cyclopropylmethyl)piperidin-2-yl]methyl}-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-(3-cyanobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione2-(biphenyl-3-ylmethyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(±)-1-[(benzyloxy)methyl]-2-(4-fluorobenzyl)4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;(±)-1-(methoxymethyl)-2-(4-fluorobenzyl)4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;(±)-1-[(allyloxy)methyl]-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;(±)-1-(ethoxymethyl)-2-(4-fluorobenzyl)4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;(±)-1-(n-propoxymethyl)-2-(4-fluorobenzyl)-4,5-dihydroxy-1,1a,2,8a-tetrahydrocyclo-propa[e]pyrido[1,2-a]pyrazine-3,7-dione;2-[1-(4fluorophenyl)ethyl]-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a]quinoxaline-6,10-dione;5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:3′,2′-e]pyrazine-6,10-dione;5-(4-fluorobenzyl)-7,8-dihydroxy-5H-pyrido[1,2-a:2′,3′-e]pyrazine-6,10-dione;and pharmaceutically acceptable salts thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 17. A method of inhibiting HIVintegrase in a subject in need thereof which comprises administering tothe subject a therapeutically effective amount of the compound accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 18. A methodfor preventing or treating infection by HIV or for preventing, treatingor delaying the onset of AIDS in a subject in need thereof whichcomprises administering to the subject a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 19. A pharmaceutical composition whichcomprises the product prepared by combining an effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 20. A combinationuseful for inhibiting HIV integrase, for treating or preventinginfection by HIV, or for preventing, treating or delaying the onset ofAIDS, which is a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda therapeutically effective amount of an HIV infection/AIDS antiviralagent selected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIVreverse transcriptase inhibitors.